WO2024118667A1

WO2024118667A1 - Eif4a1 inhibitors with antitumor activity

Info

Publication number: WO2024118667A1
Application number: PCT/US2023/081444
Authority: WO
Inventors: Ronald B. Gartenhaus; Glen E. KELLOGG; Bandish B. KAPADIA; Forum B. KAYASTHA; Noah B. HERRINGTON
Original assignee: Virginia Commonwealth University; US Department of Veterans Affairs
Current assignee: Virginia Commonwealth University; US Department of Veterans Affairs
Priority date: 2022-11-29
Filing date: 2023-11-28
Publication date: 2024-06-06
Anticipated expiration: 2025-05-29
Also published as: EP4626419A1

Abstract

The present disclosure is concerned with substituted triazole 4-carbohydrazide compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions in, for example, the treatment of cancers such as sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

EIF4A1 INHIBITORS WITH ANTITUMOR ACTIVITY CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This Application claims the benefit of U.S. Application No.63/428,429, filed on November 29, 2022, the contents of which are incorporated herein by reference in their entirety. STATEMENT REGARDING FEDERALLY FUNDED RESEARCH [0002] This invention was made with government support under grant no. R01CA164311 awarded by the National Institutes of Health and grant no. P30 CA016059 awarded by the Massey NIH-NCI Cancer Center. The government has certain rights in the invention. BACKGROUND [0003] Oncogenic signaling appears to dominate translational output at virtually every stage of cancer propagation for very specific and distinct cellular phenotypes (Sanchez-Vega F et al. (2018) Cell 173: 321-337 e310; Hagner PR, Schneider A, Gartenhaus RB. (2010) Blood 115: 2127-2135). With technological advancements, there is a growing recognition of selectivity in translational regulation mediated by core components of the mRNA biosynthetic apparatus (Truitt ML, Ruggero D. (2016) Nat Rev Cancer 16: 288-304). The regulation of messenger RNA (mRNA) translation in eukaryotic cells is critical for gene expression. It occurs principally at the initiation phase, primarily regulated by eukaryotic initiation factors (eIFs) (Pelletier et al. (2015) Cancer Res 75: 250-263). eIFs are fundamental for mRNA translation and act as the primary targets of numerous oncogenic signaling pathways to modulate gene expression. Thus, anti-tumor agents that strategically target the core components of protein synthesis, and related signaling pathways, represent novel therapeutic approaches with the potential to overcome resistance due to intra-tumor heterogeneity. [0004] The most tightly regulated step of protein biosynthesis is the initiation of cap- dependent translation in which initiation factors bind to the 5-prime (5′) 7-methylguanosine (m7G) cap of mature mRNA to launch the translation of open reading frames (Mitchell SF, et al. (2010) Mol Cell 39: 950-962.). Cap-dependent translation is driven by the canonical heterotrimeric eIF4F complex, which catalyzes ribosome recruitment to mRNA and is comprised of eIF4G (scaffold protein), eIF4E (cap-binding protein), and eIF4A (ATP- dependent RNA helicase) (Lindqvist L, et al. (2008) RNA 14: 960-969). eIF4A1 unwinds the secondary structure of RNA within the 5′ untranslated region (5'-UTR) of mRNA, a critical step necessary for the recruitment of the 43S preinitiation complex, and thus plays a vital role in initiating access to protein biosynthesis for the ribosomes (Raza F, et al. (2015) Biochem Soc Trans 43: 1227-1233). There are two mammalian isoforms of eIF4A involved in translation: eIF4A1 and eIF4A2 (Xue C, et al. (2021) Front Cell Dev Biol 9: 711965). The expression levels of eIF4A1 and eIF4A2 vary in a tissue-dependent manner. eIF4A1 is expressed more in proliferating cells compared to eIF4A2, which is dominantly expressed in growth-arrested differentiated cells, suggesting differential regulation of cell fate (Naineni SK, et al. (2020) RNA 26: 541-549). This observation that eIF4A1 and eIF4A2 have distinct biological functions in translational regulation in different subsets of cells and clinical conditions has supported the view that eIF4A1 is a rational cancer target. [0005] The plethora of biochemical data on eIF4A1 (now referred to as eIF4A) reported in the last three decades has deciphered the detailed molecular mechanism of duplex destabilization by eIF4A and the governing principles of its minimal RNA helicase activity (Andreou AZ, Klostermeier D. (2013) RNA Biol 10: 19-32). Genome-wide studies of the eIF4A-mediated translatome revealed that helicase regulates the expression of mRNAs encoding vital proteins associated with cell proliferation, cell survival, cell cycle progression, and angiogenesis (Rubio CA, et al. (2014) Genome Biol 15: 476; Wolfe AL, et al. (2014) Nature 513: 65-70). Critically, several reports emphasize that high expression levels of eIF4A significantly stimulate a cancer cell malignant phenotype (proliferation, invasion, migration, and epithelial mesenchymal transition) and inhibit apoptosis (Modelska A, et al. (2015) Cell Death Dis 6: e1603; Li W, et al. (2017) Tumour Biol 39: 1010428317698389; Liang S, et al. (2014) Int J Gynecol Cancer 24: 908-915; Gao C, et al. (2020) Acta Biochim Biophys Sin (Shanghai) 52: 310-319). Thus, the effect of eIF4A up-regulation upon transformed cells appears to act via specific messages, perhaps in addition to a global up- regulation of translation, making eIF4A an attractive target for therapeutic intervention. In addition to the expected findings that eIF4A-dependent mRNAs contained longer 5′-UTRs with a greater degree of secondary structure, both Modelska et al. and Wolfe et al. observed that 5′-UTRs of eIF4A-dependent mRNAs are enriched with G-quadruplex motifs forming potential (Rubio CA, et al. (2014) Genome Biol 15: 476; Wolfe AL, et al. (2014) Nature 513: 65-70). [0006] Several natural compounds have been characterized that inhibit cap-dependent translation by specifically inhibiting eIF4A activity. These compounds include hippuristanol (Cencic R, Pelletier J. (2016) Translation (Austin) 4: e1137381), pateamine A (PatA), and silvestrol (a rocaglate or “flavagline”) (Naineni SK, et al. (2020) RNA 26: 541-549). Rocaglate analogs are the most studied eIF4A inhibitors in the field (Chu J, et al. (2019) Cell Chem Biol 26: 1586-1593 e1583). eFT226 (zotatifin), a structure-guided rocaglamide- inspired inhibitor, has entered Phase I clinical trials for solid tumors (Ernst JT, et al. (2020) J Med Chem 63: 5879-5955). Recently, structural elucidation of a rocaglate [RocA]:eIF4A1:polypurine RNA complex revealed that rocaglates operate as interfacial inhibitors and make indispensable interactions with eIF4A1 and two adjacent RNA purine bases (Chu J, et al. (2019) Cell Chem Biol 26: 1586-1593 e1583). However, all the compounds appear to act non-specifically upon eIF4A1 and eIF4A2. Accordingly, there remains a need for compounds and compositions that selectively inhibit eIF4A1 activity. SUMMARY [0007] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to substituted triazole 4- carbohydrazides useful as, for example, eIF4A1 inhibitors. As disclosed herein, eIF4A1 inhibitors have been implicated in a variety of diseases and disorders including, but not limited to, cancers such as sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non- small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). [0008] Thus, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0009] Also disclosed are methods of modulating eIF4A1 activity in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof. [0010] Also disclosed are methods of modulating eIF4A1 activity in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof. [0011] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof. [0012] Also disclosed are kits comprising a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer. [0013] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a compound selected from: ,

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or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0014] Also disclosed are methods of modulating eIF4A1 activity in a cell, the method comprising contacting the cell with an effective amount of a compound selected from: ,

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or a pharmaceutically acceptable salt thereof. [0015] Also disclosed are methods of modulating eIF4A1 activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from: ,

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or a pharmaceutically acceptable salt thereof. [0016] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from: ,

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or a pharmaceutically acceptable salt thereof. [0017] Also disclosed are kits comprising a compound selected from: ,

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or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti- cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer. [0018] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. BRIEF DESCRIPTION OF THE FIGURES [0019] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention. [0020] FIG.1A-E show representative data illustrating the clinicopathologic evaluation of eIF4A1. [0021] FIG.2A and FIG.2B show representative data illustrating eIF4A1 expression in molecular subtypes of DLBCL in microarray datasets. [0022] FIG.3A and FIG.3B show a representative model of RocaA and a representative flow chart illustrating the process taken to identify new small molecule inhibitors for eIF4A1. [0023] FIG.4A-C show representative data illustrating the assessment of eIF4A1 in a specific luciferase assay in Hek293T/17 stables. [0024] FIG.5A-F show representative data illustrating that an eIF4A1 specific high throughput screen identifies small molecules with inhibitory effect. [0025] FIG.6A-D show representative data illustrating RBF98 activity in luciferase and biochemical assays. [0026] FIG.7A-C show representative data illustrating that RBF98 reduces proliferation and overall translation in DLBCL. [0027] FIG.8A and FIG.8B show representative images illustrating the interaction differences between RocA and docked RBF98 (FIG.8A) and a summary of the RBF98 analogs evaluated in the secondary screen (FIG.8B). [0028] FIG.9A-E show representative data pertaining to the secondary screen and the evaluation of RBF98 analogs. [0029] FIG.10A and FIG.10B show representative data illustrating the percentage inhibition of luciferase activity. Specifically, on treatment of RBF197, 203, and 208, respectively, at 0.1, 1, and 10 µM concentrations empty (FIG.10A) and blank (FIG.10B) luciferase HEK293T/17 stable cell lines. Average inhibition in relative luciferase units was not found to be more than 20% at the given concentrations. Statistical analysis was performed using one-way ANOVA followed by Bonferroni correction analysis. ^ap< 0.05; ^cp<0.001, ^dp< 0.0001 vs DMSO control groups, ^αp<0.05, ^βp<0.001, ^¥p<0.0001 vs 10 μM treatment groups. [0030] FIG.11 shows representative data illustrating that RBF197 attenuates DLBCL growth. Specifically, concentration-response curves of RBF197 in SUDHL4, OCI-Ly3, DS, and RC cell lines are shown. Linear regression fit of the inhibition values was plotted using Graph pad prism and EC₅₀ values were calculated. The EC₅₀ values were observed to be less than 10 µM. [0031] FIG.12A-G show representative data illustrating that RBF197 and RBF208 decrease overall translation and eIF4A1 dependent pathway proteins in double-hit lymphoma. [0032] FIG.13A-G show representative data illustrating that RBF197 and 208 decrease overall translation and eIF4A1 dependent pathway proteins in ABC-DLBCL OCI-Ly3 cell line. [0033] FIG.14A and FIG.14B show representative data illustrating that RBF197 and RBF208 decrease overall translation and eIF4A1 dependent pathway proteins in double-hit lymphoma. Specifically, FIG.14A shows a qRT-PCR analysis for expression of defined genes in RC following treatment of RBF197 or RBF208 at 1 and 3 µM. FIG.14B shows the relative mRNA expression data for defined genes with the treatment of RBF197 and RBF208, respectively. [0034] FIG.15A and FIG.15B show representative data illustrating the effect of RBF197 and RBF208 on DLBCL colony formation. [0035] FIG.16 shows representative docking poses of RBF197 and RBF208 in eIF4A:RNA grove. Specifically, the top two panels show schematic representations of the interactions made between docked poses of RBF197 and RBF208 and their surrounding environments. Transparent ovals are used to two-dimensionally represent possible π-π stacking interactions between the ligands and surrounding residues. Dashed lines between the ligands and surrounding residues are used to indicate hydrogen bonding. The lower two panels are high- scoring docked models of RBF197 and RBF208. [0036] FIG.17A-D show representative data illustrating that RBF 197 and RBF208 inhibit human eIF4A1 by RNA clamp mechanism. [0037] FIG.18 shows a representative schematic summary illustrating the identification of eIF4A inhibitors and RBF197 targeting eIF4A translational capacity to suppress DLBCL. [0038] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION [0039] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein. [0040] Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described. [0041] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. [0042] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation. A. D^EFINITIONS [0043] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like. [0044] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.” [0045] Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. [0046] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise. [0047] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound. [0048] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. [0049] As used herein, “IC₅₀” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an IC50 can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein. In a further aspect, IC₅₀ refers to the half-maximal (50%) inhibitory concentration (IC) of a substance. [0050] As used herein, “EC₅₀” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein. In a further aspect, EC₅₀ refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response. [0051] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. [0052] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease, disorder, or condition. The term “patient” includes human and veterinary subjects. [0053] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). [0054] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. [0055] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. [0056] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition. [0057] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the condition being treated and the severity of the condition; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition. [0058] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative. [0059] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. [0060] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates. [0061] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14^th edition), the Physicians' Desk Reference (64^th edition), and The Pharmacological Basis of Therapeutics (12^th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; anti-cancer and anti-neoplastic agents such as kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HDAc) inhibitors, iron chelotors and other ribonucleotides reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox, irinotecan, and platinum compounds, immune checkpoint blockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) mAB, cluster of differentiation 47 (CD47) mAB, toll-like receptor (TLR) agonists and other immune modifiers, cell therapeutics such as chimeric antigen receptor T-cell (CAR-T)/chimeric antigen receptor natural killer (CAR-NK) cells, and proteins such as interferons (IFNs), interleukins (ILs), and mAbs; anti-ALS agents such as entry inhibitors, fusion inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors, NCP7 inhibitors, protease inhibitors, and integrase inhibitors; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti- epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term “therapeutic agent” also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment. [0062] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner. [0063] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound. [0064] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers. [0065] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted). [0066] In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents. [0067] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0068] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s- butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl. [0069] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. [0070] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term. [0071] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. [0072] The term “polyalkylene group” as used herein is a group having two or more CH₂ groups linked to one another. The polyalkylene group can be represented by the formula — (CH₂)_a—, where “a” is an integer of from 2 to 500. [0073] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA¹—OA² or — OA¹—(OA²)a—OA³, where “a” is an integer of from 1 to 200 and A¹, A², and A³ are alkyl and/or cycloalkyl groups. [0074] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A¹A²)C=C(A³A⁴) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. [0075] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. [0076] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. [0077] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. [0078] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups. [0079] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ─NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl. [0080] The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O. [0081] The terms “amine” or “amino” as used herein are represented by the formula — NA¹A², where A¹ and A² can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH2. [0082] The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like. [0083] The term “dialkylamino” as used herein is represented by the formula —N(-alkyl)₂ where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N- ethyl-N-propylamino group and the like. [0084] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH. [0085] The term “ester” as used herein is represented by the formula —OC(O)A¹ or — C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula —(A¹O(O)C-A²-C(O)O)a— or —(A¹O(O)C-A²-OC(O))a—, where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups. [0086] The term “ether” as used herein is represented by the formula A¹OA², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula —(A¹O-A²O)_a—, where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide. [0087] The terms “halo,” “halogen,” or “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I. [0088] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups. [0089] The term “heteroalkyl,” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups. [0090] The term “heteroaryl,” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl. [0091] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3- oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2- C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring. [0092] The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl. [0093] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. [0094] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula — OH. [0095] The term “ketone” as used herein is represented by the formula A¹C(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [0096] The term “azide” or “azido” as used herein is represented by the formula —N₃. [0097] The term “nitro” as used herein is represented by the formula —NO2. [0098] The term “nitrile” or “cyano” as used herein is represented by the formula —CN. [0099] The term “silyl” as used herein is represented by the formula —SiA¹A²A³, where A¹, A², and A³ can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [00100] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A¹, —S(O)2A¹, —OS(O)2A¹, or —OS(O)2OA¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A¹S(O)2A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A¹S(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [00101] The term “thiol” as used herein is represented by the formula —SH. [00102] “R¹,” “R²,” “R³,” “Rⁿ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R¹ is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group. [00103] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted). [00104] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein. [00105] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH₂)_0–4R^o; –(CH₂)_0–4OR^o; - O(CH2)0-4R^o, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^o)2; –(CH2)0–4SR^o; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; – CH=CHPh, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R^o)2; –(CH2)0–4N(R^o)C(O)R^o; – N(R^o)C(S)R^o; –(CH2)0–4N(R^o)C(O)NR^o2; -N(R^o)C(S)NR^o2; –(CH2)0–4N(R^o)C(O)OR^o; – N(R^o)N(R^o)C(O)R^o; -N(R^o)N(R^o)C(O)NR^o ₂; -N(R^o)N(R^o)C(O)OR^o; –(CH₂)_0–4C(O)R^o; – C(S)R^o; –(CH2)0–4C(O)OR^o; –(CH2)0–4C(O)SR^o; -(CH2)0–4C(O)OSiR^o3; –(CH2)0–4OC(O)R^o; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R^o; –(CH2)0–4C(O)NR^o2; –C(S)NR^o2; – C(S)SR°; -(CH2)0–4OC(O)NR^o2; -C(O)N(OR^o)R^o; –C(O)C(O)R^o; –C(O)CH2C(O)R^o; – C(NOR^o)R^o; -(CH₂)_0–4SSR^o; –(CH₂)_0–4S(O)₂R^o; –(CH₂)_0–4S(O)₂OR^o; –(CH₂)_0–4OS(O)₂R^o; – S(O)₂NR^o ₂; -(CH₂)_0–4S(O)R^o; -N(R^o)S(O)₂NR^o ₂; –N(R^o)S(O)₂R^o; –N(OR^o)R^o; – C(NH)NR^o2; –P(O)2R^o; -P(O)R^o2; -OP(O)R^o2; –OP(O)(OR^o)2; SiR^o3; –(C1–4 straight or branched alkylene)O–N(R^o)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R^o)2, wherein each R^o may be substituted as defined below and is independently hydrogen, C_1– ₆ aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, -CH₂-(5-6 membered heteroaryl ring), or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^o, taken together with their intervening atom(s), form a 3–12– membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [00106] Suitable monovalent substituents on R^o (or the ring formed by taking two independent occurrences of R ^● together with their intervening atoms), are independently halogen, –(CH2)0–2R ^●, –(haloR ^●), –(CH2)0–2OH, –(CH2)0–2OR ^●, –(CH2)0–2CH(OR ^●)2; -O(haloR ^●), –CN, –N3, –(CH2)0–2C(O)R ^●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR ^●, –(CH2)0– 2SR ^●, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR ^●, –(CH2)0–2NR ^●2, –NO2, –SiR ^●3, –OSiR ^●3, -C(O)SR ^●, –(C1–4 straight or branched alkylene)C(O)OR ^●, or –SSR ^● wherein each R ^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ^ include =O and =S. [00107] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR^*2, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)2R^*, =NR^*, =NOR^*, –O(C(R^*2))2–3O–, or –S(C(R^*2))2–3S–, wherein each independent occurrence of R^* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR^*2)2–3O–, wherein each independent occurrence of R^* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00108] Suitable substituents on the aliphatic group of R^* include halogen, –R ^●, -(haloR ^●), -OH, –OR ^●, –O(haloR ^●), –CN, –C(O)OH, –C(O)OR ^●, –NH2, –NHR ^●, –NR ^●2, or – NO2, wherein each R ^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00109] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R^†, –NR^† ₂, –C(O)R^†, –C(O)OR^†, –C(O)C(O)R^†, –C(O)CH₂C(O)R^†, – S(O)2R^†, -S(O)2NR^†2, –C(S)NR^†2, –C(NH)NR^†2, or –N(R^†)S(O)2R^†; wherein each R^† is independently hydrogen, C_1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00110] Suitable substituents on the aliphatic group of R^† are independently halogen, –R ^●, -(haloR ^●), –OH, –OR ^●, –O(haloR ^●), –CN, –C(O)OH, –C(O)OR ^●, –NH₂, –NHR ^●, –NR ^● ₂, or –NO2, wherein each R ^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00111] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate. [00112] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999). [00113] The term “organic residue” defines a carbon-containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms. [00114] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the structure:

, regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein. [00115] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di- substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like. [00116] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers. [00117] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. [00118] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon. [00119] When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation. [00120] Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “

” forms. Conversely, “

” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms. [00121] When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof. [00122] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di-, or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem.1988, 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p.30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure. [00123] “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates. Examples of radio- actively labeled forms include compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and the like. [00124] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. [00125] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates. [00126] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid. [00127] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.

[00128] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, N¹-unsubstituted, 3-A³ and N¹-unsubstituted, 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possible tautomers. [00129] It is known that chemical substances form solids, which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms. [00130] In some aspects, a structure of a compound can be represented by a formula:

, which is understood to be equivalent to a formula:

, wherein n is typically an integer. That is, Rⁿ is understood to represent five independent substituents, R^n(a), R^n(b), R^n(c), R^n(d), R^n(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R^n(a) is halogen, then R^n(b) is not necessarily halogen in that instance. [00131] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). [00132] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification. [00133] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention. [00134] It is understood that the compounds and compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result. B. COMPOUNDS [00135] In one aspect, the invention relates to substituted triazole 4-carbohydrazide compounds useful in, for example, the treatment of cancer. Exemplary cancers for which the disclosed compounds can be useful include, but are not limited to, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). Thus, in one aspect, the compounds of the invention are useful in the treatment of cancer as further described herein. [00136] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1. STRUCTURE [00137] In one aspect, disclosed are compounds having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof. [00138] Also disclosed are compounds selected from:

,

_,

, ,

,

or a pharmaceutically acceptable salt thereof. [00139] In various aspects, the compound has a structure represented by a formula:

, wherein R² is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof. [00140] In various aspects, the compound has a structure represented by a formula:

, wherein each of R^20a, R^20b, R^20c, R^20d, and R^20e is independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰, or a pharmaceutically acceptable salt thereof. In a further aspect, R¹ is methyl. In a still further aspect, each of R^20a, R^20b, R^20c, R^20d, and R^20e is independently selected from hydrogen and ‒OH. In yet a further aspect, R^20a is ‒OH. [00141] In various aspects, the compound has a structure represented by a formula:

, or a pharmaceutically acceptable salt thereof. [00142] In various aspects, the compound is selected from: ,

,

,

or a pharmaceutically acceptable salt thereof. [00143] In various aspects, the compound is selected from: ,

or a pharmaceutically acceptable salt thereof. a. R¹ AND R² GROUPS [00144] In one aspect, each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R¹ and R² is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R¹ and R² is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R¹ and R² is independently selected from hydrogen and ethyl. In an even further aspect, each of R¹ and R² is independently selected from hydrogen and methyl. [00145] In various aspects, R¹ is selected from hydrogen and C1-C4 alkyl. In a further aspect, R¹ is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R¹ is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R¹ is selected from hydrogen and ethyl. In an even further aspect, R¹ is selected from hydrogen and methyl. [00146] In various aspects, R¹ is C1-C4 alkyl. In a further aspect, R¹ is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R¹ is selected from methyl and ethyl. In yet a further aspect, R¹ is ethyl. In an even further aspect, R¹ is methyl. [00147] In various aspects, R¹ is hydrogen. [00148] In various aspects, R² is selected from hydrogen and C1-C4 alkyl. In a further aspect, R² is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R² is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R² is selected from hydrogen and ethyl. In an even further aspect, R² is selected from hydrogen and methyl. [00149] In various aspects, R² is C1-C4 alkyl. In a further aspect, R² is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R² is selected from methyl and ethyl. In yet a further aspect, R² is ethyl. In an even further aspect, R² is methyl. [00150] In various aspects, R² is hydrogen. b. R¹⁰ G^ROUPS [00151] In one aspect, R¹⁰, when present, is selected from hydrogen and C1-C4 alkyl. In a further aspect, R¹⁰, when present, is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R¹⁰, when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R¹⁰, when present, is selected from hydrogen and ethyl. In an even further aspect, R¹⁰, when present, is selected from hydrogen and methyl. [00152] In various aspects, R¹⁰, when present, is C1-C4 alkyl. In a further aspect, R¹⁰, when present, is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R¹⁰, when present, is selected from methyl and ethyl. In yet a further aspect, R¹⁰, when present, is ethyl. In an even further aspect, R¹⁰, when present, is methyl. [00153] In various aspects, R¹⁰, when present, is hydrogen. c. AR¹ GROUPS [00154] In one aspect, Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰. In a further aspect, Ar¹ is selected from C6- C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰. In a still further aspect, Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In yet a further aspect, Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In an even further aspect, Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is unsubstituted. [00155] In various aspects, Ar¹ is C6-C12 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰. In a further aspect, Ar¹ is C6-C12 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰. In a still further aspect, Ar¹ is C6-C12 aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰. In yet a further aspect, Ar¹ is C6-C12 aryl monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In an even further aspect, Ar¹ is unsubstituted C6-C12 aryl. [00156] In various aspects, Ar¹ is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In a further aspect, Ar¹ is C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰. In a still further aspect, Ar¹ is C6 aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰. In yet a further aspect, Ar¹ is C6 aryl monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In an even further aspect, Ar¹ is unsubstituted C6 aryl. [00157] In various aspects, Ar¹ is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰. [00158] In various aspects, Ar¹ is phenyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰. [00159] In various aspects, Ar¹ is phenyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, methyl, methoxy, and ‒CO₂H. In a further aspect, Ar¹ is phenyl substituted with a ‒OH. [00160] In various aspects, Ar¹ is C5-C11 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰. In a further aspect, Ar¹ is C5-C11 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In a still further aspect, Ar¹ is C5-C11 heteroaryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In yet a further aspect, Ar¹ is C5-C11 heteroaryl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In an even further aspect, Ar¹ is unsubstituted C5-C11 heteroaryl. [00161] In various aspects, Ar¹ is selected from thiophenyl, furanyl, and pyridinyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In a further aspect, Ar¹ is selected from thiophenyl, furanyl, and pyridinyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In a still further aspect, Ar¹ is selected from thiophenyl, furanyl, and pyridinyl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In yet a further aspect, Ar¹ is selected from thiophenyl, furanyl, and pyridinyl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰. In an even further aspect, Ar¹ is selected from thiophenyl, furanyl, and pyridinyl, and is unsubstituted. 2. EXAMPLE COMPOUNDS [00162] In one aspect, a compound can be present as:

,

_,

,

^,

or a pharmaceutically acceptable salt thereof. [00163] In one aspect, a compound can be present as: ,

or a pharmaceutically acceptable salt thereof. [00164] In one aspect, a compound can be present as:

,

_,

,

^,

or a pharmaceutically acceptable salt thereof. C. P^{HARMACEUTICAL} C^OMPOSITIONS [00165] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00166] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a compound selected from:

,

_,

, ,

,

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00167] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, intravenous, topical, or oral administration. [00168] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990. [00169] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [00170] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds. [00171] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. [00172] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques. [00173] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. [00174] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [00175] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. [00176] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof. [00177] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency. [00178] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds. [00179] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form. [00180] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount. [00181] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient. [00182] In a further aspect, the pharmaceutical composition is used to treat cancer. In a still further aspect, the cancer is a primary or secondary tumor. In yet a further aspect, the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix. In an even further aspect, the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non- small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). [00183] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. D. METHODS OF MAKING A COMPOUND [00184] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein. [00185] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Routes I-IV, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting. 1. ROUTE I [00186] In one aspect, substituted triazole 4-carbohydrazide compounds can be prepared as shown below. SCHEME 1A.

[00187] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 1B.

[00188] In one aspect, compounds of type 1.4, and similar compounds, can be prepared according to reaction Scheme 1B above. Thus, compounds of type 1.4 can be prepared by oxidation of an appropriate amine, e.g., 1.3 as shown above. Appropriate amines are commercially available or prepared by methods known to one skilled in the art. The oxidation is carried out in the presence of an appropriate nucleophile, e.g., sodium azide, an appropriate oxidant, e.g., sodium nitrite, and an appropriate acid, e.g., sulphuric acid. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1), can be substituted in the reaction to provide substituted oxadiazole compounds similar to Formula 1.2. 2. ROUTE II [00189] In one aspect, substituted triazole 4-carbohydrazide compounds can be prepared as shown below. SCHEME 2A.

[00190] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 2B.

[00191] In one aspect, compounds of type 2.6, and similar compounds, can be prepared according to reaction Scheme 2B above. Thus, compounds of type 2.6 can be prepared by nucleophilic addition and cyclization of an appropriate azide, e.g., 2.4 as shown above, and an appropriate alkyl 4-halo-3-oxobutanoate, e.g., 2.5 as shown above. Appropriate alkyl 4- halo-3-oxobutanoates are commercially available or prepared by methods known to one skilled in the art. The nucleophilic addition/cyclization is carried out in the presence of an appropriate inorganic salt, e.g., magnesium carbonate, in an appropriate solvent, e.g., ethanol, for an appropriate period of time, e.g., 3 hours, at an appropriate temperature, e.g., reflux. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1 and 2.2), can be substituted in the reaction to provide substituted triazole carboxylate compounds similar to Formula 2.3. 3. ROUTE III [00192] In one aspect, substituted triazole 4-carbohydrazide compounds can be prepared as shown below. SCHEME 3A.

[00193] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 3B.

[00194] In one aspect, compounds of type 3.6, and similar compounds, can be prepared according to reaction Scheme 3B above. Thus, compounds of type 3.6 can be prepared by nucleophilic addition of an appropriate triazole carboxylate, e.g., 3.4 as shown above, and an appropriate triazolthione, e.g., 3.5 as shown above. Appropriate triazolthiones are commercially available or prepared by methods known to one skilled in the art. The nucleophilic addition is carried out in the presence of an appropriate base, e.g., sodium bicarbonate, in an appropriate solvent, e.g., ethanol, for an appropriate period of time, e.g., 3 hours, at an appropriate temperature, e.g., reflux. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.1 and 3.2), can be substituted in the reaction to provide substituted triazole carboxylate compounds similar to Formula 3.3. 4. ROUTE IV [00195] In one aspect, substituted triazole 4-carbohydrazide compounds can be prepared as shown below. SCHEME 4A.

[00196] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 4B.

[00197] In one aspect, compounds of type 4.8, and similar compounds, can be prepared according to reaction Scheme 4B above. Thus, compounds of type 4.6 can be prepared by hydrazinolysis of an appropriate ester, e.g., 4.5 as shown above. The hydrazinolysis is carried out in the presence of an appropriate hydrazine, e.g., hydrazine hydrate, in an appropriate solvent, e.g., ethanol, at an appropriate temperature, e.g., room temperature to 60 °C. Compounds of type 4.8 can be prepared by nucleophilic addition of an appropriate hydrazine, e.g., 4.6, and an appropriate carbonyl derivative, e.g., 4.7. Appropriate carbonyl derivatives are commercially available or can be prepared by methods known to one of skill in the art. The nucleophilic addition is carried out in the presence of an appropriate acid, e.g., hydrochloric acid, in an appropriate solvent, e.g., ethanol, at an appropriate temperature, e.g., room temperature. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 4.1, 4.2, and 4.3), can be substituted in the reaction to provide substituted triazole 4-carbohydrazide compounds similar to Formula 4.4. E. METHODS OF MODULATING EIF4A1 ACTIVITY IN A CELL [00198] In one aspect, disclosed are methods of modulating eIF4A1 activity in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof. [00199] Also disclosed are methods of modulating eIF4A1 activity in a cell, the method comprising contacting the cell with an effective amount of a compound selected from: ,

,

_,

,

^,

or a pharmaceutically acceptable salt thereof. [00200] In various aspects, modulating is inhibiting. [00201] In various aspects, the cell is a cancer cell. [00202] In various aspects, the cell is present in a tissue sample. In various further aspects, the tissue sample is a malignant tissue sample. [00203] In various aspects, the cell is human. In various further aspects, the cell has been isolated from a human prior to the contacting step. [00204] In various aspects, contacting is via administration to a subject. In various further aspects, the subject has been diagnosed with a need for modulation of eIF4A1 activity prior to the administering step. In various further aspects, the subject has been diagnosed with a need for treatment of cancer prior to the administering step. F. METHODS OF MODULATING EIF4A1 ACTIVITY IN A SUBJECT [00205] In one aspect, Also disclosed are methods of modulating eIF4A1 activity in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof. [00206] Also disclosed are methods of modulating eIF4A1 activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from: ,

,

_,

,

^,

or a pharmaceutically acceptable salt thereof. [00207] In various aspects, the subject is a mammal. In various further aspects, the subject is a human. [00208] In various aspects, the subject has been diagnosed with a need for modulating eIF4A1 activity prior to the administering step. In various further aspects, the subject has been diagnosed with a need for treatment of a disorder related to eIF4A1 activity prior to the administering step. [00209] In various aspects, the disorder is cancer. G. METHODS OF TREATING CANCER [00210] In one aspect, disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof. Examples of cancers for which the disclosed compounds, compositions, and methods can be useful include, but are not limited to, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). [00211] Thus, in one aspect, disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof. [00212] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from: ,

,

_,

,

^,

or a pharmaceutically acceptable salt thereof. [00213] In a further aspect, the subject has been diagnosed with a need for treatment of cancer prior to the administering step. In a still further aspect, the subject is at risk for developing cancer prior to the administering step. [00214] In a further aspect, the subject is a mammal. In a still further aspect, the mammal is a human. [00215] In a further aspect, the method further comprises the step of identifying a subject in need of treatment of cancer. [00216] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount. [00217] In a further aspect, the cancer is a primary or secondary tumor. In a still further aspect, the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix. In yet a further aspect, the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non- small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). [00218] In a further aspect, administering is oral or parental administration. In a still further aspect, the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection. [00219] In a further aspect, the method further comprises administering a therapeutically effective amount of an anti-cancer agent or radiotherapy to the subject. In a still further aspect, the anti-cancer agent or radiotherapy is administered prior to administration of the compound. In yet a further aspect, the anti-cancer agent or radiotherapy is administered subsequent to administration of the compound. [00220] In a further aspect, the method further comprises administering to the subject an effective amount of at least one anticancer agent. Examples of anticancer agents include, but are not limited to, doxorubicin, cisplatin, 5-fluorouracin (5-FU), etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, and oxaliplatin. [00221] In a further aspect, the compound and the agent are administered sequentially. In a still further aspect, the compound and the agent are administered simultaneously. [00222] In a further aspect, the compound and the agent are co-formulated. In a still further aspect, the compound and the agent are co-packaged. [00223] In a further aspect, the compound is administered as a single active agent. H. ADDITIONAL METHODS OF USING THE COMPOUNDS [00224] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). [00225] To treat or control the condition, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of cancer such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). [00226] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). [00227] The therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. 1. USE OF COMPOUNDS [00228] In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for the treatment of cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanomas, gliomas, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). [00229] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In a further aspect, the compound used is a product of a disclosed method of making. [00230] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, for use as a medicament. [00231] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making. [00232] In various aspects, the use relates to a treatment of cancer. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the cancer is a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non- small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). [00233] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of cancer in a mammal. In a further aspect, the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). 2. MANUFACTURE OF A MEDICAMENT [00234] In one aspect, the invention relates to a method for the manufacture of a medicament for treating cancer in a subject having the condition, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent. [00235] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of cancer (e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, or plasma cell neoplasm (myeloma). The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable timeframe. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal. [00236] The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 0.05 mg/kg and about 100 mg/kg of body weight for mice, and more preferably between 0.05 mg/kg and about 50 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight for humans, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months. [00237] The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations. [00238] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or diluent. 3. KITS [00239] In one aspect, disclosed are kits comprising a disclosed compound, and one or more selected from: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer. [00240] Thus, in one aspect, disclosed are kits comprising a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1- C4 alkyl, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer. [00241] Also disclosed are kits comprising a compound selected from: ,

,

,

,

or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti- cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer. [00242] In a further aspect, the kit comprises the anti-cancer agent. Examples of anti- cancer agents include, but are not limited to, alkylating agents, antimetabolite agents, antineoplastic antibiotic agents, mitotic inhibitor agents, DNA damage-inducing agents, and mTor inhibitor agents. [00243] In a further aspect, the kit comprises an antineoplastic antibiotic agent. Examples of antineoplastic antibiotic agents include, but are not limited to, doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof. [00244] In a further aspect, the kit comprises an antimetabolite agent. Examples of antimetabolite agents include, but are not limited to, gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof. [00245] In a further aspect, the kit comprises an alkylating agent. Examples of alkylating agents include, but are not limited to, carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof. [00246] In a further aspect, the kit comprises a mitotic inhibitor agent. Examples of mitotic inhibitor agents include, but are not limited to, irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof. [00247] In a further aspect, the kit comprises an mTor inhibitor agents. Examples of mTor inhibitor agents include, but are not limited to, everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt thereof. [00248] In a further aspect, the kit comprises a DNA damage-inducing agent. Examples of DNA damage-inducing agents include, but are not limited to, doxorubicin, cisplatin, 5-Fluorouracin, etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, and oxaliplatin (or pharmaceutically acceptable salts thereof) and ionizing radiation. [00249] In a further aspect, the compound and the agent are co-formulated. In a further aspect, the compound and the agent are co-packaged. [00250] In a further aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises an effective amount of the compound and the anti-cancer agent. In a still further aspect, the effective amount is a therapeutically effective amount. In yet a further aspect, the effective amount is a prophylactically effective amount. In an even further aspect, each dose of the compound and the anti-cancer agent are co-formulated. In a still further aspect, each dose of the compound and the anti-cancer agent are co-packaged. [00251] The kits can also comprise compounds and/or products co-packaged, co- formulated, and/or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient. [00252] It is understood that the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using. [00253] The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments. [00254] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls. I. E^XAMPLES [00255] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. [00256] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way. 1. METHODS a. MOLECULAR MODELING STUDIES [00257] Prior to virtual screening, the crystal structure of the eIF4A1 complexed with a polypurine mRNA and RocA (PDB ID: 5ZC9) was obtained from the RCSB Protein Data Bank (Berman HM, et al. (2000) Nucleic Acids Res 28: 235-242). RocA pharmacophore- based virtual screening of the MolPort and ZINC15 databases was conducted using the Unity module of the Sybyl-X 2.1.1 suite using its “Flex Search” option. All docking studies were conducted in Genetic Optimisation for Ligand Docking (GOLD) (Jones G, et al. (1997) Mol Biol 267: 727-748) using the built-in ChemPLP scoring function. The high-throughput docking of our virtual screening hits was performed with aromatic ring center constraints and hydrogen bond donor and acceptor constraints, according to their positions in the original virtual screening pharmacophore. Higher-resolution dockings allowed at least 50 solutions per ligand while maintaining all but the original hydrogen bond donor constraints. Post- docking steepest descent energy minimizations were conducted using the Tripos force field in Sybyl-X 2.1.1 with a gradient of 0.02 kcal/mol, 100,000 iterations, Gasteiger-Hückel charges, and a dielectric constant of 8.0. Secondary scoring of eIF4A1-ligand complexes was conducted using the Hydropathic INTeractions (HINT) force field (Kellogg GE, et al. (1991) J Comput Aided Mol Des 5: 545-552; Eugene Kellogg G, Abraham DJ. (2000) Eur J Med Chem 35: 651-661). b. CELL CULTURE AND TRANSFECTIONS [00258] Cells were procured from ATCC (DS, RC, Toledo, Farage, SUDHL-2, SUDHL-4) and DSMZ (OCI-Ly3). GMO B-cells (lymphoblastoid cells) were purchased from the National Institutes of General Medical Sciences Human Genetic Mutant Cell Repository (Coriell Institute for Medical Research, Camden, NJ, USA). All DLBCL and GMO cells were grown in Roswell Park Memorial Institute (RPMI)-1640 except OCI-Ly3, grown in Iscove's Modified Dulbecco's Medium (IMDM) with 10% FBS (Corning, Fetal Bovine Serum), and were maintained at 37 °C with 5% CO₂. Hek293T/17 was cultured in Dulbecco's Modified Eagle Medium (DMEM) with 10% FBS. Stable cells (293T) were generated by PEI-mediated transfection, selected, and maintained with puromycin (1 mg/mL). Post selection, cells were cultured in DMEM containing 10% FBS. Cells were regularly passaged according to prescribed guidelines. Exponentially growing cells were treated with selected inhibitors and maintained at 37 °C, harvested at indicated time points for further analysis. The quality and authenticity of cell lines were performed regularly using regular mycoplasma testing and short tandem repeat(STR) profiling through the Nucleic Acid Research Facilities (NARF) at Virginia Commonwealth University (VCU), compared against known STR profiles. c. REAGENTS [00259] RBF series small molecules were procured from MolPort, Inc platform, silvestrol: Medchem express, WST1: Dojindo Molecular Technologies Inc, phenazine ethosulfate, DMSO: Sigma-Aldrich, D-Luciferin, potassium Salt: Gold Biotechnology. All the other chemicals were procured from Fisher Scientific. d. LUCIFERASE ASSAYS [00260] Four tandem repeats of the (CGG)412-mer motif (GQs) or random sequence matched for length and GC content (random) were cloned into the pLenti-5’UTR-Luciferase (Wolfe AL, et al. (2014) Nature 513: 65-70). Empty firefly luciferase plasmid pLenti- 5’UTR-Luc or blank with random sequence were used as controls (Wolfe AL, et al. (2014) Nature 513: 65-70). Briefly, after indicated treatments, cells were lysed in Triton Lysis Buffer (Baker JM, Boyce FM. (2014) High-throughput functional screening using a homemade dual-glow luciferase assay. J Vis Exp.). The cell lysate was mixed with luciferase assay reaction buffer (Kapadia B, et al. (2013) PLoS One 8: e83787), and luminescence was measured on a luminometer (Synergy H.T.X., Multi-Mode Reader). e. CELL PROLIFERATION AND VIABILITY BY WST -1 [00261] Cell titrations were performed for optimal cell numbers. Five thousand cells for activated B-cell (ABC) DLBCL and 10,000 cells for germinal center B-cell (GCB) DLBCL were seeded in 96 well formats in 90 µL media. Cells were incubated for 24 h at 37 °C and 5% CO₂. Compounds were dissolved in an appropriate solvent. Dilutions of compound (0.1, 0.3, 1, 3, 10, 30, 100, and 300 µM) were prepared containing stock concentration of 1% DMSO (10X).10 µL of stock compound was added to each well in triplicates for each group and incubated for 72 h at 37 °C and 5% CO2 for the proliferation assay (Final concentration of the compounds: 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 µM).10 µL/well cell proliferation reagent (WST-1 (2 mg/mL), phenazine ethosulfate solution (0.21 mg/mL) dissolved in 1X PBS) was added and incubated for 1.5 h at 37 °C and 5% CO₂ (Koyanagi M, Kawakabe S, Arimura Y. (2016) A comparative study of colorimetric cell proliferation assays in immune cells. Cytotechnology 68: 1489-1498). Absorbance was measured at 450 nm using a microplate (Synergy H.T.X., Multi-Mode Reader) reader. f. ASSESSMENT OF VIABLE CELLS [00262] Exponentially growing cells were seeded in equal density (1 million). Post 12 h of seeding, cells were collected to the indicated time points and stained with trypan blue. The number of non-viable and viable cells was counted depending upon the intake of trypan blue in the hemocytometer using Thermo Fisher Countess III Automated Cell Counter (Kapadia B, et al. (2018) Nat Commun 9: 829). g. PHOSPHATE RELEASE ASSAY [00263] A colorimetric assay to measure the phosphate released during ATP hydrolysis based on Malachite green was used to measure the activity of human eIF4A1 (1913204, ABM). The reaction buffers contained 50 mM potassium acetate, 20 mM MES pH6.0, 2 mM dithiothreitol (DTT), 0.1 mg/mL BSA and 100 ng/mL of whole yeast RNA (Type XI-C, Sigma-Aldrich) (Abdelkrim YZ, et al. (2018) Mol Biochem Parasitol 226: 9-19). The compounds were incubated at various concentrations with 20 ng human eIF4A1 in a reaction buffer for 30 min. Reactions were started by adding 50 µM ATP and then incubated at 37 °C for 2 h. Reactions were stopped by adding the solutions ∼60 mM in ethylenediaminetetraacetic acid (EDTA). The absorption at 630 nm was converted to phosphate concentration by a reference curve generated from a dilution series of a known phosphate concentration (1 mM Pi standard; SensoLyte® MG Phosphate Assay Kit Colorimetric). Reaction velocities were determined by a linear regression fit of the phosphate generated against time. Only the initial linear phases of the curves were used. Velocities were determined for at least three independent experiments for each reaction condition. h. RNA UNWINDING ASSAY [00264] Custom-made RNA oligonucleotides were procured from Integrated DNA Technologies (IDT). RNA unwinding assay was undertaken with minor modifications as previously described (Andreou et al. (2017) RNA Biol 14: 113-123). Duplex RNA (5 µM) for unwinding reactions was prepared by annealing a 32mer RNA modified with cyanine 5 (Cy5) at its 5’-end (5’Cy5- CGAGG UCCCA AGGGU UGGGC UGUUC GCCCA UU-3’) and a complementary 9mer modified with a cyanine 3 (Cy3) at the 3’-end (5’-UUGGGACCU- Cy3–3’) in 25 mM Hepes/KOH, pH 7.4. The mixture was heated to 96 ºC for 2 min, slowly cooled to room temperature, and incubated on ice for 15 min. A 9-nucleotide loop connecting the duplex strands was introduced for the single turnover condition. Experiments were performed in 30 mM HEPES/KOH pH 7.4, 100 mM KOAc, 3 mM Mg(OAc)₂, 2 mM DTT at 25 ºC with 100 nM duplex RNA, a 10-fold molar excess of unlabeled 9mer RNA to trap the released 9mer (5’-AGG UCC CAA-3’), and 5 µM of human eIF4A1. The compounds were incubated with human eIF4A1 for 30 min at 25 ºC. Unwinding reactions were initiated by adding 1 mM ATP after obtaining a stable fluorescence signal. Kinetic readings were captured for 30 min. (The stability of the signal was noted at 3 min; however, to ensure that the reaction is complete, i.e., all molecules bound with eIF4A RNA complex, the reading was taken until 30 min.) Post 30 min, another duplex (100 nM) was added to the mixture, and an increase in the fluorescence was measured after 3 min. Second readings (3 min after the second duplex was added) were normalized with the first reading (30 min). Here the assumption is that the compound will clamp eIF4A: RNA complex and hampers the recycling of enzymes for its helicase activity. Thus, the enzyme that is freely available for the activity will act on the newly added substrate. Excess molar ATP was used (50 µM for phosphatase assay compared to 1 mM in this assay). All measurements were conducted in an Infinite® 200 PRO (Tecan). Cy3 fluorescence was excited at 554 nm (1 nm bandwidth), and Cy5 fluorescence was detected at 666 nm (3 nm bandwidth) in 10 s intervals with an integration time of 0.1 s. All measurements were repeated at least three times, and the increase in the fluorescence was calculated in the presence or absence of the inhibitors. i. SURFACE SENSING OF TRANSLATION (SUNSET) ASSAY [00265] SUnSET assay was performed as per the manufacturer's recommendations (Kerafast) as previously reported (Kapadia B, et al. (2018) Nat Commun 9: 829). In brief, cells were pulse-labeled with puromycin (1 µg/mL) for 30 min. Post-treatment, cells were washed with ice-cold PBS, lysed, and probed (10 µg of protein) with an anti-puromycin antibody. Signals were normalized by indicated loading control in each set. j. IMMUNOBLOTTING [00266] Cells were lysed in RIPA buffer (50 mM TRIS pH 7.5, 150 mM NaCl, 0.1% SDS, 0.5% sodium deoxycholate, 1% triton X-100, 1 mM EDTA, and 1 mM EGTA, 1 mM sodium orthovanadate, 1 mM sodium fluoride, 1× protease inhibitor (Sigma-Aldrich), phosphatase inhibitor cocktails #2 and #3 (Sigma-Aldrich), and 1 mM PMSF)(27). Cells lysate were quantified using Bradford reagents and equal amount of protein was separated on a BOLT 4–12% Bis-Tris gradient gel (Life Technologies) and probed with the following antibodies: eIF4A (sc-377315 or sc-14211, 1:1000), eIF4E (SCBT, sc-9976, 1:1000), cMyc (SCBT, sc-373712 or SC-764, 1:1000), Bcl2 (CST # 2870 or SCBT, sc-509, 1:1000), Bcl6 (CST, #5650, 1:1000), Parp-1 (SCBT, sc-7150, 1:1000), Actin (SCBT, sc-1615, 1:1000), Gapdh (Abcam, ab8245, 1:10,000), Vinculin (Sigma, V9131, 1:10,000), Cdk7 (sc-529, 1:1000) Nrf2 (CST, #12721, 1:1000) and Card11 (CST, #4435, 1:1000). Densitometry analyses were performed using Image Studio (Licor Biosciences) and presented as ratio of target band signal intensity to Gapdh/Actin/Vinculin band signal intensity. k. CLONOGENIC METHYLCELLULOSE ASSAYS [00267] Lymphoblastoid cells (GMO 17220B, 1528, 13604), DLBCL cells (ABC- DLBCL: OCI-Ly3, DS, and GCB-DLBCL: Farage, RC, Toledo) cell lines were utilized for colony formation assay. Briefly, cells (25–50 × 10³) were mixed methylcellulose (RnD) conditioned IMDM with 20% FBS (Kapadia B, et al. (2018) Nat Commun 9: 829). Cells were then treated with the respective compounds or DMSO, and colonies were visualized and counted at 15-day post treatment. l. IMMUNOHISTOCHEMISTRY [00268] To study the expression pattern of the eIF4A1 protein, immunohistochemical staining was performed using Biocare Medical Intellipath F.L.X. auto-stainer. Briefly, tissue microarray (TMA) slides (US Biomax, LY1001B, LY1001C E069, LM801280, Y10001D SD43 and LY800B B040) were baked at 65 ºC and deparaffinized (X1-10 min, X2-10 min) by using Xylene (Fisher Scientific) and subsequently hydrated by sequential incubation in ethanol (100% EtOH-5 min, 70% EtOH-5 min, 50% EtOH-5 min, H2O-5 min). Antigen retrieval was performed using a Decloaking Chamber™ NxGen (Biocare Medical) with pre- heated 1X Borg Declokar buffer (Biocare Medical, USA) at 95 ºC for 30 min. Slides were then loaded into the Intellipath FLX™ machine, and blocking of the endogenous peroxidase was performed by incubation with intelliPATH FLX™ Peroxidase Blocking Reagent (Biocare Medical) for 10 min. Later tissue sections were blocked with intelliPATH™ Background Punisher (Biocare Medical) for 5 min and incubated with the primary antibodies against anti-eIF4A1 (1:200) (rabbit monoclonal ab31217; Abcam, Cambridge, MA) for 1 h (Zhao Y, et al. (2021) Cancer Cell Int 21: 670). The sections were washed with TBS Automation Wash Buffer (Biocare Medical) and incubated with MACH 2 Universal HRP- Polymer polymer (Biocare Medical) for 30 min. Immunoreactivity was visualized by intelliPATH FLX™ DAB Chromogen Kit (Biocare Medical) followed by intelliPATH™ Hematoxylin (Biocare Medical) counterstain and mounted with EcoMount (Biocare Medical). Based on the staining intensity, samples were scaled between 1 and 4, as discussed earlier (1 means low staining intensity while 4 represents the highest staining intensity) (Kapadia BB, et al. (2022) PARK2 regulates eIF4B-driven lymphomagenesis. Mol Cancer Res). m. ANALYSIS OF EIF4A1 EXPRESSION IN PUBLICLY AVAILABLE DLBCL DATASETS [00269] UACLAN (http://ualcan.path.uab.edu/) is an extensive resource to evaluate tumor data, primarily The Cancer Genome Atlas (TCGA). The expression of eIF4A1 in TCGA DLBCL samples (n=41) was extracted using the UACLAN database (Chandrashekar DS, et al. (2017) Neoplasia 19: 649-658; Chandrashekar DS, et al. (2022) Neoplasia 25: 18- 27). eIF4A1 in naive B cells was obtained from healthy individuals (n = 91) from the DICE [Database of Immune Cell Expression, Expression quantitative trait loci (eQTLs), and Epigenomics] database, which is a comprehensive resource of expression and epigenomic profiles of different types of human immune cells (Schmiedel BJ, et al. (2018) Cell 175: 1701-1715 e1716). The expression of eIF4A1 was also mined in other publicly-available DLBCL datasets (Schmitz R, et al. (2018) N Engl J Med 378: 1396-1407), GSE10846 (Lenz G, et al. (2008) N Engl J Med 359: 2313-2323; Cardesa-Salzmann TM, et al. (2011) Haematologica 96: 996-1001) and GSE87371 (Dubois S, et al. (2017) Clin Cancer Res 23: 2232-2244; Dubois S, et al. (2019) EBioMedicine 48: 58-69). Finally, prognostic implications of eIF4A1 in DLBCL were assessed using the Genomic Data Commons (GDC) dataset (Schmitz R, et al. (2018) N Engl J Med 378: 1396-1407). n. QUANTITATIVE REVERSE TRANSCRIPTION REAL-TIME POLYMERASE CHAIN REACTION [00270] RNA was extracted from DLBCL cells using TRIzol (Invitrogen Corporation). cDNA was reverse transcribed from 1000 ng RNA using the High-Capacity RNA-to- cDNA™ Kit (Thermo Scientific). All primer sequences included in the study are listed in Table 1. Quantitative reverse transcription real-time polymerase chain reaction (qRT-PCR) methods were developed on a Power SYBR Green Master Mix (Thermo Scientific) according to the manufacturer's instructions. The mRNA expressions were analyzed using the 2−ΔCT method (Kain V, et al. (2015) Sci Rep 5: 15197). TABLE 1.

o. STATISTICS [00271] Data were analyzed using GraphPad Prism 9. Values were expressed as mean ±S.D. of a minimum of three independent experiments. Wilcoxon signed-rank test was used to compare the data sets between naïve GCB B-cells and DLBCL samples; p<0.05 was considered significant. The unpaired Student’s t-test was used to compare the two groups. One-way ANOVA followed by either Dunnett’s or Bonferroni’s post hoc analysis compared more than two groups; p <0.05 was considered significant. Hill coefficient was calculated for the concentration-response curves. 2. R^ESULTS a. EXPRESSION OF EIF4A1 PREDICTS POOR OUTCOME IN DIFFUSE LARGE B CELL LYMPHOMA. [00272] To elucidate the pathophysiological relevance of eIF4A1 in DLBCL, the publicly available datasets were examined. Analyzing the expression profile of eIF4A1 in the Database of Immune Cell Expression (DICE), Expression quantitative trait loci (eQTLs), Epigenomics (Schmiedel BJ, et al. (2018) Cell 175: 1701-1715 e1716) and The Cancer Genome Atlas (TCGA) (Chandrashekar DS, et al. (2017) Neoplasia 19: 649-658) datasets, a robust increase (p<0.0001) in the transcript levels of eIF4A1 was observed in DLBCL samples compared to naïve B-cells (FIG.1A), supporting the relevance of eIF4A1 in lymphomagenesis. Given the substantial variability and unique heterogeneity/biology within DLBCL, this lymphoma subgroup is further classified as Activated B-cell (ABC), Germinal Center B-cell (GCB), and Unclassified (UNC) DLBCL based on its expression profile (Menon MP, et al. (2012) Cancer J 18: 411-420). In support of this observation, ABC- DLBCL cohorts (n=260) (which have a worse outcome with standard immune-chemotherapy compared to GCB-DLBCL (Nowakowski GS, Czuczman MS. (2015) Am Soc Clin Oncol Educ Book: e449-457) display higher expression of eIF4A1 compared to GCB-DLBCL (n=138) (p=0.032) or UNC-DLBCL (n=104) (p=0.191) (FIG.1B). In agreement with these data, transcriptomic profiles (GSE10846(36) and GSE87371 (Dubois S, et al. (2019) EBioMedicine 48: 58-69) showed that eIF4A1 mRNA was expressed at a higher level in ABC-DLBCL (n=250) compared with GCB-DLBCL (n=268) or UNC-DLBCL (n=64) (FIG. 2A-B). To further validate this observation, primary DLBCL specimens from commercially procured DLBCL tissue microarrays (US Biomax., Inc) were stained. In coherence with the above data, the protein levels of eIF4A1 were robustly detected in DLBCL samples (n=377) compared to Reactive Lymph Nodes (LN) (n=54) (FIG.1C). Staining DLBCL samples displayed 72% expression of eIF4A1 while that of reactive lymph node was 33%. Collectively, eIF4A appears to be upregulated in DLBCL. [00273] Referring to FIG.1A, representative plots showing RNA-seq expression profiles of eIF4A1 in naïve B-cells (n=91) (obtained from DICE database https://dice- database.org/) compared with DLBCL (n=41) in TCGA dataset are shown. eIF4A1 showed significantly higher expression in tumor samples compared with control. The Y-axis represents transcript per million (TPM) values. ****p<0.0001 [00274] Referring to FIG.1B, a comparison of RNA-seq data of eIF4A1 in molecular subgroups using a publicly available large dataset of patients with DLBCL is shown. eIF4A1 showed significantly higher expression in ABC-DLBCL (n=260) subgroups compared with GCB-DLBCL (n=138) and UN-DLBCL (n=104), *p<0.05. The values are represented in log base 2 of fragments per kilobase of exon per million mapped fragments (FPKM). [00275] Referring to FIG.1C, a representative immunohistochemistry image of commercially procured (US Biomax., Inc) TMA slides stained with eIF4A1 antibody is shown. Representative scatter plots showing the stained signals of eIF4A1 in reactive LN compared to DLBCL samples. Statistical analysis was performed using Wilcoxon signed- rank test (unpaired two-tailed), ****p < 0.001 vs. reactive LN. Summary chart for DLBCL and normal LN. -ve: no staining detected, low: 1–2 staining density, high: 3–4 staining density. [00276] Referring to FIG.2A, eIF4A1 expression was found to be significantly (***p<0.001) higher in ABC-DLBCL subtypes compared to GCB and UN-DLBCL in the microarray dataset GSE10846. A similar trend was observed in the GSE87371 dataset p=0.203 (FIG.2B). [00277] To further investigate the clinical importance of eIF4A1 in lymphoma progression, the prognostic value of eIF4A1 gene expression was determined using publicly available datasets (Chandrashekar DS, et al. (2017) Neoplasia 19: 649-658; Chandrashekar DS, et al. (2022) Neoplasia 25: 18-27; Schmiedel BJ, et al. (2018) Cell 175: 1701-1715 e1716), employing a cox p-value<0.05. As shown in FIG.1D and FIG.1E, eIF4A1 was significantly associated with overall survival (OS) and progression-free survival (PFS) of patients with DLBCL. Patients with a higher median expression of eIF4A1 showed shorter survival periods than those with lower median expression. (FIG.1D, n=206, p=0.039). Consistently, patients with higher expression of eIF4A1 have a shorter progression-free interval than patients with low expression of eIF4A1 (FIG.1E, n=206 p=0.019). Altogether, the above clinical data endorses the claim that higher eIF4A1 gene expression is associated with poor survival and more aggressive clinicopathological features, supporting the notion that eIF4A1 is a promising therapeutic target in DLBCL. [00278] Referring to FIG.1D, eIF4A1 expression was found to be significantly (p=0.039) associated with OS of patients with DLBCL in the publicly available dataset (n=206). Patients with a lower median expression of eIF4A1 showed a better prognosis than patients having higher median expression. [00279] Referring to FIG.1E, eIF4A1 expression was also found to be significantly (p=0.019) associated with the PFS in the same cohort of patients with DLBCL having a similar observation. b. STRUCTURE-BASED DRUG SCREEN IDENTIFIES NEW INHIBITORS OF EIF4A1 [00280] The search for novel inhibitors of eIF4A1 began with a structure-based virtual screen of a potential binding site of eIF4A1. Using a crystal structure (PDB ID: 5ZC9 (Iwasaki S, et al. (2019) Mol Cell 73: 738-748 e739)) of eIF4A1 complexed with a polypurine mRNA strand and RocA, which is a natural product inhibitor of eIF4A. To establish what features of RocA to use for the basis of the virtual screen, the HINT force field was utilized (Kellogg GE, et al. (1991) J Comput Aided Mol Des 5: 545-552; Eugene Kellogg G, Abraham DJ. (2000) Eur J Med Chem 35: 651-661) to determine the molecular features of RocA most responsible for its binding. Briefly, HINT is a scoring function based on the free energy associated with solvent partitioning between 1-octanol and water. It has been used in numerous studies involving interactions between and amongst proteins, polynucleotides, and small molecules (Obaidullah AJ, et al. (2018) Chem Biodivers 15: e1800234; Spyrakis F, et al. (2013) PLoS One 8: e77558; Chen D, et al. (2008) Bioorg Med Chem 16: 7225-7233). In addition to π-π stacking interactions between the mRNA bases of the polypurine strand and with PHE163 in literature reported by Iwasaki et al. (Iwasaki S, et al. (2019) Mol Cell 73: 738-748 e739), two key hydrogen-bonding interactions involving the ligand and GLN195, as well as G8, were noted (FIG.3A). Table 2 lists these crucial interactions that were concluded to contribute most to RocA’s binding and activity. [00281] Referring to FIG.3A, a model of RocaA used to define important pharmacophore features used in pharmacophore-based virtual screening experiment is shown. TABLE 2.

[00282] The hydrogen bond between O6 of RocA and G8 of the mRNA is consistent with Iwasaki et al.’s structural studies. Thus, the aromatic rings of RocA, along with its acceptor O1 and donor O6, were used as pharmacophore features in a virtual screen for new inhibitors (FIG.3B). Virtual screening was performed using the ‘Flex Search’ option of the Unity (Hurst T. (1994) Journal of Chemical Information and Computer Sciences 34: 190- 196) suite in Sybyl-X 2.1.1. A total of 1218 hits from the screen underwent high-throughput docking in GOLD 5.6.1 with 20 solutions per ligand. All solutions were triaged into the HINT force field for secondary scoring. The top 29 scoring compounds (Table 3) from HINT were purchased and further assayed for activity. [00283] Referring to FIG.3B, a workflow for the virtual screening strategy that identified RBF98 as the top hit is shown. Stages for this workflow included obtaining the crystal structure of eIF4A1 complexed with RocA, scoring interactions between these two species, constructing and implementing the virtual screening pharmacophore, high- throughput molecular docking, energy minimizations of solutions, preliminary scoring of solutions in HINT, and final energy minimizations and scoring, followed by the purchase of the 29 top-scoring hits TABLE 3.

[00284] To rapidly evaluate the inhibitory ability of the selected novel eIF4A inhibitors, an in-cell high throughput eIF4A-3X luciferase assay was used (Wolfe AL, et al. (2014) Nature 513: 65-70). The luciferase-based reporter assay with 5’UTR of eIF4A- sensitive four tandem repeats of the (CGG)₄12-mer motif (GQs) driven by beta-actin promoter was used as a platform for primary screening in Hek293T/17 stables cell lines (FIG.4A). Cofactors like eIF4B stimulate the activity of eIF4A1. However, the eIF4A regulated luciferase readout was minimally dependent on eIF4B (FIG.4B). Similar experiments were performed with silvestrol as an internal control (FIG.4C), suggesting that the consensus sequence is highly reliant on eIF4A. The 29 commercially available hit compounds were used for the initial primary screen at concentrations ranging from 1 nM to 10 µM. Luciferase readout greater than 50% was considered the cut-off value for the screen. RBF98 showed around 50% inhibition with respect to the DMSO control at 1 nM concentration (FIG.5A-C). Interestingly, the percentage decrease in the luciferase readout was less than 10% in blank and empty luciferase groups, suggesting high specificity for the compound (FIG.6A) in limiting eIF4A-driven translation. It should be noted that the compound RBF98, at higher concentrations, showed a decrease in eIF4A inhibition, probably due to various physicochemical properties such as reduced solubility, etc. The ability of compound RBF98 to preferentially target eIF4A-sensitive luciferase with a readout similar to silvestrol provides promising evidence that RBF98 inhibits eIF4A and not another protein in the general translational apparatus and also binds in a manner similar to silvestrol. After analyzing its highest-scoring docked pose, it was concluded that RBF98 might adopt a similar binding mode to RocA, with three of its aromatic rings forming π-π stacking interactions with two adjacent nucleotide bases and PHE163, which seem to be crucial for rocaglate activity. Further, this docked pose of RBF98 shows that its phenoxide moiety may form a hydrogen bond with G8 of the RNA strand and a novel ionic interaction between its ammonium group and ASP198. This previously unobserved interaction may be integral for achieving improved drug-like properties over rocaglamate-based inhibitors (FIG.8A). Additional biochemical testing was performed with RBF98 to investigate the direct inhibition of the compound on eIF4A’s helicase activity. Here, an inorganic phosphate release assay was run to directly measure the eIF4A1 ATP-dependent RNA helicase activity using a stable mixture of yeast RNA. To achieve a maximal signal-to-noise ratio in this endpoint assay, the amount of enzyme and the incubation time were optimized (FIG.6B-C). RBF98 showed a dose- dependent decrease with an inhibitory effect at ~50% at a concentration of 0.3 µM compared with the DMSO control (FIG.6D). [00285] Referring to FIG.4A, the design of a luciferase construct with 5’UTR of eIF4A1 G- quadruplex sequence with the β-actin promoter, negative controls, blank with scrambled sequence and empty test construct is shown. [00286] Referring to FIG.4B, eIF4A-3X-luciferase expressing 293T cells were transfected with shRNA against eIF4A1 and eIF4B followed by luciferase readout. Statistics were performed using Dunnett's Test. A significant decrease was observed in relative luciferase units in eIF4A1 shRNA groups. ****p<0.0001 vs non-transfected cells. [00287] Referring to FIG.4C, various dose treatments of silvestrol in eIF4A1-3X, blank and empty luciferase Hek293T/17 stables, were evaluated. Percentage inhibition in the reduction of luciferase was calculated relative to DMSO control. The IC₅₀ value was observed to be 10 nM. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis. ^ap< 0.05; ^cp<0.001, ^dp< 0.0001 vs DMSO control groups, ^αp<0.05, ^βp<0.001, ^¥p<0.0001 vs 1μM or 10μM treatment groups. [00288] Referring to FIG.5A, a scatterplot of primary screen results is shown. A total of 29 compounds were tested and luciferase signal reduced by ≥50% compared to control were identified and considered active. Luciferase activity results are expressed relative to values obtained in the presence of vehicle controls. Percentage inhibition was calculated and plotted in a scatter plot, n=3 biological replicates performed Mean±SEM. [00289] FIG.5B shows the structure of RBF98, a candidate inhibitor, and FIG.5C shows the percentage inhibition observed in the treatment of RBF98 at various concentrations in eIF4A1-3X-Luciferase Hek293T/17. [00290] Referring to FIG.6A, the percentage inhibition of luciferase activity on treatment with RBF98 at 0.1, 1, and 10 µM concentrations in empty/blank luciferase HEK293T/17 stable cell lines is shown. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis. ^ap< 0.05; ^cp<0.001, ^dp< 0.0001 vs DMSO control groups, ^αp<0.05, ^βp<0.001, ^¥p<0.0001 vs 10μM treatment groups. [00291] Referring to FIG.6B, eIF4A1 titration and measurement of phosphate release with 50 μM ATP and 100 ng/ml of yeast RNA is shown. Referring to FIG.6C, ATP titration was used to select linear range concentration in the presence of 20 ng of eIF4A1 and 100 ng/ml yeast RNA. [00292] Referring to FIG.6D, dose-dependent percentage inhibition of human eIF4A1 in-vitro activity on the treatment of RBF98 was compared to DMSO control using an inorganic phosphate release assay (SensoLyte kit). IC50 values observed were observed to be 3 µM. [00293] Referring to FIG.8A, interaction environments for RocA and RBF98 are shown. The top two panels show stick representations of the interactions made between RocA and RBF98 and their surrounding environments. Transparent ovals are used to two- dimensionally represent possible π-π stacking interactions between the ligands and surrounding residues. Dashed lines between the ligands and surrounding residues are used to indicate hydrogen bonding. [00294] Next, RBF98’s impact on a cellular proliferation assay was analyzed. The compound reduced the cellular proliferation of DLBCL cells at 0.5 µM and 1 µM concentrations. Silvestrol was again used as a positive control (FIG.7A). Cellular proliferation at lower concentrations had minimal impact on DLBCLs (data not shown). For further insight into the effect of RBF98, a colony formation assay was performed in the OCI- Ly3, Toledo (malignant cell lines) and lymphoblastoid cells (GMO 17220B, 1528, 13604, non-malignant cell lines). It was observed that RBF98 significantly decreases colony formation in malignant cell lines in a dose-dependent manner (FIG.5D-E and FIG.7B). Notably, treatment of lymphoblastoid cells had minimal impact on their proliferative capacity indicating that the compound may have a potential non-toxic effect on non-malignant cells, addressing a major limiting factor of the currently available eIF4A inhibitors (FIG.5D, FIG. 5F, and FIG.7B). To further explore the molecular insights of RBF98’s activity, DLBCL cells were pulse-labeled with puromycin after treatment with the compound. Immunoblotting with anti-puromycin revealed a concentration-dependent decrease of puromycin labeling along with the protein levels of eIF4A, but minimal changes in eIF4E, indicating an overall reduction in the translation capacity of the cells (FIG.7C). Further, the expression of eIF4A- dependent genes, cMYC (Zhang X, et al. (2020) Leukemia 34: 138-150) and CyclinD1 (Stoneley M, Willis AE. (2015) Cell Death Differ 22: 524-525) was reduced similarly (FIG. 7C). [00295] Referring to FIG.5D, the effect of RBF98 on DLBCL colony formation is shown. Representative image of the colony formation in OCI-Ly3 (malignant) and GMO17220B (non-malignant) cells. The total number of colonies grown in OCI-Ly3 (FIG. 5E) and GMO17220B (FIG.5F) cells upon treatment with 0.5 and 1 µM of RBF98. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis. ^ap< 0.05; ^cp<0.001, ^dp< 0.0001 vs DMSO control groups, ^αp<0.05, ^βp<0.001, ^¥p<0.0001 vs 1 mM RBF98 treated groups. [00296] Referring to FIG.7A, for proliferation assay, Farage (GCB) origin was seeded at a density of 10,000 and treated with 0.5 and 1 µM of RBF98 for up to 72 hours. The cell viability was measured at different time points using the trypan blue method. Silvestrol treatment was done at 50 nM as a positive control group. Viability was observed to be decreasing with increasing time in comparison to DMSO control (^ap< 0.05; ^cp<0.001, ^dp< 0.0001). [00297] Referring to FIG.7B, the effect of RBF98 on DLBCL colony formation is shown. Specifically, the data illustrate the total number of colonies grown in Toledo (malignant), GMO1528, and GMO13604 (non-malignant) cells on treatment with 0.5 and 1 mM of RBF98. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis. ^ap< 0.05; ^cp<0.001, ^dp< 0.0001 vs DMSO control groups, ^αp<0.05, ^βp<0.001, ^¥p<0.0001 vs 1 mM treatment groups. [00298] Referring to FIG.7C, puromycin (1 μg/mL) was exposed, post compound treatments for 30 minutes (SUnSET assay), and cells (Toledo and OCI-LY3) were lysed. Representative immunoblots probed with anti-puromycin, anti- eIF4A1, anti-eIF4E, anti- cMYC, anti-CyclinD1. GAPDH was used as the loading control. [00299] After screening the initial set of 29 compounds, analogs of RBF98 were pursued in the hope of identifying purchasable compounds with better or comparable activity to it, the most potent hit. Using a similarity search function based on Tanimoto indices (Rogers DJ, Tanimoto TT. (1960) Science 132: 1115-1118) built into the MolPort website, 34 analogs were identified (Table 4) that had chemical similarities to RBF98. Generally, the compounds from this round of screening structurally differed in three positions from RBF98, which allowed for aspects of the structure-activity relationship of the hit to be probed (FIG. 8A). Alteration of these positions was focused on because they were the most accessible changes based on the collection of compounds commercially available from MolPort. FIG. 8B illustrates some of the different structural variations in these positions. After the luciferase readout, the primary screen was applied to the 34 compounds obtained, RBF197, RBF203, and RBF208 (FIG.9A and FIG.9B), which displayed a dosage-dependent decrease in luciferase readout (FIG.9C). More importantly, all three hit molecules do not show more than 15% inhibition of blank (FIG.10B) and empty luciferase readout (FIG.10A), implicating a specific inhibitory effect on eIF4A dependent activity. Most of the compounds available for purchase from the virtual screen and that were assayed showed alterations to the m-phenoxide moiety of RBF98, thus allowing for this region to be probed extensively (FIG. 8B). The other two regions of the RBF98 first-round lead remain largely unexplored. [00300] Referring to FIG.9A, a total of 34 compounds that inhibited Luciferase signal by ≥50% compared to control were identified. Luciferase activity results are expressed relative to values obtained in the presence of vehicle controls. Percentage inhibition was calculated and plotted in a scatter plot, n=3 biological replicates performed Mean±SEM. FIG.9B shows the structures of RBF197, RBF203, and RBF208, potent candidate inhibitors. FIG.9C shows representative plots of percentage inhibition values of luciferase activity on the treatment of RBF 197, RBF203, and RBF208 at 0.1, 1, and 10 µM in eIF4A1-3X- Luciferase in Hek293T/17 cell lines for 24 h (n=3). Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis. ^ap< 0.05; ^cp<0.001, ^dp< 0.0001 vs DMSO control groups, ^αp<0.05, ^βp<0.001, ^¥p<0.0001 vs 10 μM treatment groups. TABLE 4.

[00301] To further corroborate these findings, these three new hits were subjected to a kinetic assessment using an in vitro inorganic phosphate assay. Surprisingly, the selected three compounds potently inhibited eIF4A helicase activity in a dose-dependent manner with IC50 values in the picomolar range and with Hill coefficients 1.35, 1.33, and 1.75, indicating single-molecule binding without aggregating effects (FIG.9D and FIG.9E). [00302] Referring to FIG.9D, concentration-response curves of percentage inhibition of human eIF4A1 in-vitro activity on the treatment of RBF197, RBF203, and RBF208, compared to DMSO control by measurement of inorganic phosphate released (SensoLyte Kit) are shown. IC50 values observed were 55.2, 208.8, and 74.1 pM, respectively. FIG.9E shows the Hill coefficient values for the concentration-response curves. c. NOVEL EIF4A INHIBITOR BLOCKS CELL PROLIFERATION AND IMPEDES OVERALL TRANSLATION IN DLBCL [00303] To determine if the most potent compounds exert inhibitory activity in DLBCLs, a panel of DLBCL cells were subjected to a WST -1 cell viability assay. This assay quantitates the number of living and metabolically active cells by measuring the cleavage of tetrazolium salts by intracellular enzymes. As shown in Table 5, all the hit compounds decreased the cellular viability of DLBCL cells with a half maximal effective concentration (EC50) in the low micromolar range (FIG.11). Surprisingly, SUDHL2, which harbors a mutation in A20, SOCS1, and TP53, was insensitive to the eIF4A inhibitors (Juskevicius D, et al. (2018) Leuk Lymphoma 59: 1710-1716). Additional analogs with varying potencies in the luciferase readout assays were tested in the cell viability assay to investigate if helicase inhibition tracked DLBCL WST1 inhibition, and to ensure that cell viability did not decrease due to the general toxicity of the inhibitor scaffold (Table 6). As anticipated, these molecules do not dramatically affect the DLBCL cellular viability; thus, minor substitution to our selected compounds that hampers their eIF4A inhibitory capacity also displays a minor reduction in potency of DLBCL cellular viability. TABLE 5.

TABLE 6.

[00304] Next, two compounds, RBF197 and RBF208, were tested for their detailed mechanistic profiling on eIF4A-dependent transcripts in DLBCL. A cellular translation assay was performed to confirm the ability of these molecules to impede cellular protein biosynthetic machinery and to correlate the cellular viability by small molecules to eIF4A inhibition. DLBCLs RC (GCB, Double-Hit) and OCI-LY3 (ABC) cell lines were treated with the compounds for 16 hours, followed by a pulse labeling for 30 minutes with puromycin. Inhibiting eIF4A activity in DLBCL cells showed a significant dose-dependent decrease in overall protein translation output (FIG.12A-B and FIG.13A-B). The protein levels of eIF4A, but not eIF4E1, showed a dosage-induced decrease (FIG.12A-B and FIG.13A-B). Interestingly, minor alterations in the transcript levels of eIF4A1 were noted post-treatment (FIG.13C and FIG.14A). [00305] Referring to FIG.12A, SUnSET assay was performed by exposing cells to puromycin (1 μg/mL), post compound treatments for 30 min, and subsequently lysed. Representative immunoblots were probed with anti-puromycin, anti-eIF4A1, and anti-eIF4E. GAPDH was probed as an internal loading control. Referring to FIG.12B, relative fold change in expression levels with on treatment of RBF197 or RBF208 at 1 and 3 µM concentrations. [00306] Referring to FIG.13A, representative immunoblots probed with anti- puromycin, anti-eIF4A1, and anti-eIF4E are shown. FIG.13B and FIG.13C show the relative fold change in protein levels with on treatment of RBF 197 (FIG.13B) or RBF208 (FIG.13C) at 1 and 3 µM concentrations with respect to the DMSO control. GAPDH was used as a loading control. [00307] Due to the significant reduction in cellular proliferation coupled with decreased nascent peptide biosynthesis upon compound treatments, the eIF4A-sensitive genes were interrogated. Several target oncogenes, including cMYC (Wilmore S, et al. (2021) Cell Mol Life Sci 78: 6337-6349), MCL1 (Wilmore S, et al. (2021) Cell Mol Life Sci 78: 6337- 6349), and CARD11 (Steinhardt JJ, et al. (2014) Blood 124: 3758-3767), are well-established eIF4A-dependent oncogenes. Furthermore, genes like CDK7 (Zhao X, et al. (2019) Cancer Cell 35: 752-766 e759), NRF2 (Sanghvi VR, et al. (2021) NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy. Cancers (Basel) 13), and PARP1 (Parvin S, et al. (2019) Cancer Cell 36: 237-249 e236) are established chemoresistance markers for various therapies in B-cell lymphoma. As expected, the expression of cMYC, MCL1, and CARD11 was noted to be sensitive to eIF4A activity (FIG.12C-D and FIG.13D-E). Surprisingly, emerging chemo-resistant markers, CDK7, PARP1, and NRF2, also decreased dose-dependently (FIG.12C-D and FIG.13D-E). Unlike previous studies (Sanghvi VR, et al. (2021) NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy. Cancers (Basel) 13; Peters TL, et al. (2018) Clin Cancer Res 24: 4256-4270), no significant changes in the protein levels of Cyclin E and BCL2 were observed upon eIF4A inhibition (FIG.12C-D and FIG.13D-E). Furthermore, the mRNA levels of all the above-mentioned oncogenes were minimally modified (FIG.13D and FIG.14B). To determine the relative importance of the eIF4A inhibitor in the translation of different mRNAs, the translational efficiency of most of the mRNAs studied herein were investigated. As shown in FIG.12E, a heat map summarizes the protein/transcript ratio revealed a population of genes with substantially diminished translation upon the compound treatment (FIG.13G). [00308] Given that eIF4A inhibitors demonstrated a statistically significant reduction in cell proliferation in DLBCL subtypes as well as depletion of critical oncogenes, a colony formation assay was next performed with a panel of DLBCL and lymphoblastoid cells. We selected seven different cell lines; five are of DLBCL (ABC (Hagner PR, et al. (2010) Blood 115: 2127-2135) or GCB (Truitt ML, Ruggero D. (2016) Nat Rev Cancer 16: 288-304)) origin, while the other two are non-malignant cell lines (lymphoblastoid, GMO). In agreement with previous data, a significant dose-dependent decrease in the number of colonies formed was observed. Notably, RBF 197 displayed minimal effect on colony formation in GMO cell types, while RBF 208 reduced colony formation in GMO cell lines at a higher concentration (FIG.12F-G and FIG.15A-B). These results are consistent with RBF197 and RBF208 being selective eIF4A inhibitors, while the therapeutic window for RBF197 is broader than RBF208. [00309] Referring to FIG.12C, representative immunoblots of cMYC, MCL1, PARP1, BCL2, CDK7, NRF2, Cyclin E, and CARD11 on treatment with RBF197 and RBF208 at 1 and 3 µM concentrations, respectively, are shown. Vinculin was used as a loading control. FIG.12D shows the relative fold change in protein levels of the above- mentioned proteins with on treatment of RBF197 or RBF208, respectively. [00310] Referring to FIG.12E, a heat map of translation efficiency values for RBF197 and RBF208 in RC cell line is shown. FIG.12F shows the effect of RBF197 and RBF208 on DLBCL colony formation. Representative image of the colony formation in RC (malignant) and GMO13604 (non-malignant) cells is shown. [00311] Referring to FIG.12G, the total number of colonies grown in RC and GMO13604 cells upon treatment with 1 and 3 µM of RBF197 and RBF 208, respectively, is shown. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis. ^ap< 0.05; ^cp<0.001, ^dp< 0.0001 vs DMSO control groups, ^αp<0.05, ^βp<0.001, ^¥p<0.0001 vs 3 μM treatment groups. [00312] Referring to FIG.13D, representative immunoblots of indicated antibodies on treatment with RBF197 and 208 at 1 and 3 µM concentrations, respectively, are shown. Vinculin was used as a loading control. FIG.13E and FIG.13F show the relative fold change in protein levels of the above-mentioned proteins with on treatment of RBF197 (FIG. 13E) and RBF208 (FIG.13F), respectively. [00313] Referring to FIG.13G, the relative mRNA expression data for defined genes with the treatment of RBF197 and RBF208, respectively, is shown.36B4 was used as a housekeeping gene. Results were normalized with DMSO controls and expressed as mean±SD (n=3). Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis. ^ap< 0.05; ^cp<0.001, ^dp< 0.0001 vs DMSO control groups, ^αp<0.05, ^βp<0.001, ^¥p<0.0001 vs 3 μM treatment groups. [00314] Referring to FIG.15A and FIG.15B, the total number of colonies grown in Farage, SUDHL4, DS, OCI-Ly3 (malignant), and GMO17220B (non-malignant) cell lines upon treatment with 1 and 3 µM of RBF197 (FIG.15A) and RBF208 (FIG.15B), respectively, is shown. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s correction analysis. ^ap< 0.05; ^cp<0.001, ^dp< 0.0001 vs DMSO control groups, ^αp<0.05, ^βp<0.001, ^¥p<0.0001 vs 3μM treatment groups. d. P^OTENTIAL RNA ^{CLAMP MECHANISM OF E}IF4A ^INHIBITION [00315] To account for the increased activities seen for RBF197 and RBF208, more extensive docking studies were performed for these compounds. Not surprisingly, considering their flexibility and the size/shape of the pocket, a wide variety of high-scoring docked poses were obtained for these compounds. Although many other high-scoring docked poses were obtained, it was hypothesized that the poses of FIG.16 are highly probable, as their aromatic ring systems and interactions with GLN195 are consistent with the defined pharmacophore from the original virtual screen, which in turn was based on the RocA-bound crystal structure (Iwasaki S, et al. (2019) Mol Cell 73: 738-748 e739) of eIF4A1. Also, the pose shown for RBF197 was the most reasonable since this hit was notably more potent than the others, which is believed to be attributed to a crucial hydrogen bond between the eIF4A1:RNA complex and the protonated, in this case, phenoxide moiety of the scaffold (FIG.8A and FIG.16). [00316] The modeling studies suggested that RocA’s and the compounds’ mechanism of action involves trapping and distorting RNA’s bound pose. Indeed, RocA’s crystallized conformation positions itself such that it inserts between the A7 and G8 bases and binds on top of the bound RNA (FIG.3A). From the results of the virtual screen, it is believed that the hit compounds bind similarly because they, too, have three aromatic rings capable of forming π-π stacking interactions (FIG.8A and FIG.16). It is speculated that such molecules trap the eIF4A: RNA complex. To experimentally confirm this, a functional RNA unwinding assay was employed to measure the activity of human eIF4A1 recombinant protein in the presence or absence of the inhibitors. Here, the RNA stable duplex was formed by annealing 32mer RNA modified with cyanine 5 (Cy5) at its 5′-end and a complementary 9mer modified with a cyanine 3 (Cy3) at the 3′-end (FIG.17A). A stable fluorescence was recorded. A 10-molar excess of unlabeled 9mer was added to the reaction to ensure a single turnover of the RNA unwinding. The reaction was started by adding excess ATP in the presence or absence of compounds. An increase in fluorescence readout was observed in the compound-treated samples compared to DMSO (this was considered basal) (FIG.17B). To assess whether the compounds stably locked the eIF4A: RNA duplex, an additional fluorescent-labeled stable RNA complex was added, and the kinetic values were measured. The values were subsequently normalized and converted to percentage inhibition with respect to DMSO control groups. As proposed, the rate of RNA unwinding of the eIF4A: RNA duplex post- compound treatment was drastically reduced, with the IC₅₀ value observed to be upper nanomolar range (FIG.17C). The assay results represent the potential RNA-eIF4A-inhibitor complex formation, which diminishes eIF4A1’s helicase activity. [00317] Referring to FIG.17A, a schematic depiction of the fluorescent duplex unwinding assay is shown. Briefly, a 32-mer RNA strand is modified on its 5′ end with cyanine 5 (Cy5) and annealed to a complimentary loading strand that is modified on its 3′ end 9-mer with cyanine 3 (Cy3). The 9-mer RNA strand released upon unwinding was trapped by an unlabeled 9-mer DNA oligonucleotide to give single turnover reactions. [00318] Referring to FIG.17B, a four-step protocol is shown, including (1) duplex formation (5 µM) by heating at 96 °C for 2 min and cooling on ice for 5 min; (2) reading of stable fluorescence at 0 minutes with or without compound in presence of human eIF4A1, unlabeled 9mer, and additional duplex; (3) addition of ATP and recording of kinetic reading for 30 min; (4) post 30 min, again adding duplex and reading the fluorescence intensity after 3 min. [00319] Referring to FIG.17C and FIG.17D, the difference in the increase in the fluorescence was calculated in the presence and absence of RBF197 (FIG.17C) and RBF208 (FIG.17D). Concentration-response curves were plotted using a graph pad prism and IC₅₀ was observed at 0.7 and 0.9 µM respectively. 3. DISCUSSION [00320] Translation initiation, particularly eIF4A RNA helicase, is emerging as a privileged chemotherapeutic target as numerous studies associate it with the rate of protein biosynthesis, tumor initiation, chemoresistance, cancer stem cell functions, and metastasis (Fabbri L, et al. (2021) Nat Rev Cancer 21: 558-577; Park E-H, et al. (2019) Clinical Lymphoma, Myeloma and Leukemia 19: e129; Lee LJ, et al. (2021) Trends Cancer 7: 134- 145; Chan K, et al. (2019) Nat Commun 10: 5151). While current and previous studies (Raza F, et al. (2015) Biochem Soc Trans 43: 1227-1233; Andreou AZ, Klostermeier D. (2013) RNA Biol 10: 19-32; Liang S, et al. (2014) Int J Gynecol Cancer 24: 908-915; Kapadia B, et al. (2018) Nat Commun 9: 829) support the concept that eIF4A is critical in lymphomagenesis, the clinical utility of selective eIF4A inhibitors has been limited to date. Several potent small molecules have been identified, including natural molecules like rocaglates and elatol, demonstrating potent anticancer activity both in vitro and in vivo. However, none of these compounds has found success in the clinic (Naineni SK, et al. (2020) RNA 26: 541-549; Chu J, et al. (2019) Cell Chem Biol 26: 1586-1593 e1583; Peters TL, et al. (2018) Clin Cancer Res 24: 4256-4270; Chu J, Pelletier J. (2018) Therapeutic Opportunities in Eukaryotic Translation. Cold Spring Harb Perspect Biol 10).An important exception is eFT226, a promising candidate undergoing Phase I clinical trials with the data still pending (Ernst JT, et al. (2020) J Med Chem 63: 5879-5955). Resistance and relapse to frontline therapy in DLBCL still presents a major clinical issue. Therefore, the successful development of eIF4A-selective small molecules inhibitors as a drug target, may open up new options for therapy of this most common adult lymphoma. Significantly, most potent eIF4A inhibitors, including eFT226, exhibit a common rocaglate backbone, raising the question of whether this chemical backbone is associated with the limiting toxicity. Furthermore, RocA is also reported to bind with prohibitin 1 and 2, thus impeding c-Raf induced MAPK/ERK pathways, raising the question about the specificity of this class of small molecules (Chu J, et al. (2016) Cell Rep 15: 2340-2347). [00321] The publicly available information about eIF4A1-RocA structure was utilized, and a structure-guided approach was designed to develop RocA-independent potent eIF4A small molecule inhibitors to address these shortcomings. Three compounds, RBF197, RBF203, and RBF208, that hamper in vitro eIF4A helicase activity (IC₅₀ ≤ 250 pM) were successfully identified. Furthermore, through selective replacement of a specific phenoxide moiety, critical mechanistic insights were gained into the mode of action for these small molecules to exert their inhibition. Lastly, it was demonstrated that novel eIF4A inhibitors significantly hamper eIF4A-dependent target genes in biologically relevant DLBCL cells (FIG.18). [00322] This study began with a survey of the RocA binding site of a RocA::RNA::eIF4A1 co-crystallized complex. Using the HINT force field, several key interactions were identified and attributed to RocA’s tight binding to the RNA::eIF4A1 complex, including three π-π stacking and two different hydrogen-bonding interactions. These major interactions were utilized as features for a ligand pharmacophore-based virtual screen for novel eIF4A inhibitors.1218 hits were obtained from the screen, which underwent high-throughput docking in GOLD using the original pharmacophore features as docking constraints. The top 29 best scoring compounds were purchased for primary screening. Based on the previously established screening protocol targeting eIF4A1, a luminometric method was developed for screening eIF4A activity assay by measuring the eIF4A-sensitive 5’UTR driven luciferase readout (Wolfe AL, et al. (2014) Nature 513: 65-70). This method is simple, sensitive, robust, and in-cell, providing quick and reliable outputs. Comparatively, all the other small molecules targeting eIF4A have been screened using in vitro assays (Naineni SK, et al. (2020) RNA 26: 541-549; Abdelkrim YZ, et al. (2018) Mol Biochem Parasitol 226: 9- 19). The preliminary screen noted RBF98 impeding 50% luciferase inhibition at 1 nM concentration in the luciferase-based assay while having minimal impact on control assays (FIG.6A). Next, it was run through an in vitro assay, and it was observed that the compound inhibits ~50% of eIF4A helicase activity around 3 μM. Potential new interaction sites were identified, like ASP198 and the known RocA binding sites of PHE163. This is important to note because the docking studies suggest that the most potent compounds from the screen utilize similar features as rocaglates for binding and additional ones that may improve its selectivity for eIF4A1 and drug-like properties. Without wishing to be bound by theory, the bountiful information obtained from the docking studies will further guide the design of new, more potent compounds. [00323] Using these insights, a rational approach was utilized to search for procurable chemical mimetics of RBF98. These efforts led to the identification of three potent small molecule inhibitors: RBF197, RBF203, and RBF208. All three hits showed a remarkable selective decrease in luciferase assays. Notably, biochemical activity assays demonstrated compounds that are active at picomolar concentrations, which is believed to be the first report of eIF4A1 inhibitory activity at this potency. More importantly, all the three novel molecules displayed robust inhibition in cellular proliferation of DLBCLs with EC50 ranging in lower micromolar concentrations. [00324] Next, the study was extended to delineate the mechanistic profiling of eIF4A- dependent transcripts in DLBCL using the MYC/BCL2 DLBCL cell line (RC (Pham LV, et al. (2015) J Hematol Oncol 8: 121)) and the ABC-DLBCL cell line (OCI-LY3 (Wenzel SS, et al. (2013) Leukemia 27: 1381-1390)). As anticipated, the compounds were effective in blocking translational output in DLBCL (Kapadia B, et al. (2018) Nat Commun 9: 829). In fact, RBF197 and RBF208 showed a dose-dependent decrease in eIF4A-dependent oncogenes (cMYC (Wilmore S, et al. (2021) Cell Mol Life Sci 78: 6337-6349), MCL1 (Wenzel SS, et al. (2013) Leukemia 27: 1381-1390), and CARD11 (Steinhardt JJ, et al. (2014) Blood 124: 3758-3767)). NRF2 is a redox master regulator induced by oncogenic KRAS regulating the transcriptional program of specific translational factors for efficient protein synthesis (Chio IIC, et al. (2016) Cell 166: 963-976). Further, a recent report indicates that NRF2 activation, an emerging prognostic indicator in DLBCL (Yi X, et al. (2018) Exp Ther Med 16: 573-578), confers resistance to silvestrol analog in cancer therapy (Chio IIC, et al. (2016) Cell 166: 963-976). In contrast, treatment with novel identified eIF4A inhibitors, we noted a dose-dependent decrease of NRF2 was noted at the protein levels. Recent evidence suggests that intramolecular KRas-NRF2 axis are involved in stress granules formation, which are emerging as a key indicator of chemoresistance (Mukhopadhyay S, et al. (2020) Cancer Res 80: 1630-1643). Given that the cancer cells are exposed to adverse conditions both in the tumor micromovement and during chemotherapy, stress granules utilizes the post transcriptional control mechanism to re-program gene expression for enhancing cellular survivability (Zhan Y, et al. (2020) Am J Cancer Res 10: 2226-2241; Anderson P, et al. (2015) Biochim Biophys Acta 1849: 861-870). Importantly, enhanced activity of eIF4A has been reported to reduce RNA condensation and thus limiting stress granules formation under favorable cellular proliferative conditions (Tauber D, et al. (2020) Cell 180: 411-426 e416). Given the observation that eIF4A inhibitors limit the expression of NRF2, future studies will focus on understanding the impact of RBF197/203 on RNA condensation and stress granules activities. Similarly, CDK7, a critical cell cycle modulator deregulated in cMYC and BCL6 dependent DLBCL (Lacrima K, et al. (2007) Leuk Lymphoma 48: 158-167), was also depleted upon the compound treatment. Likewise, PARP1, a DNA binding protein associated with DNA damage repair that confers resistance to genotoxic compounds routinely used as chemotherapeutic agents (Hu Y, et al. (2018) Leukemia 32: 2250-2262), was also noted to decline in DLBCL cells. Along with genotoxic stress, there is a growing appreciation for understanding the metabolic phenotypes imposed by harsh cancerous conditions for exploring personalized medicine approach to target metabolism in cancer (Martinez-Reyes I, Chandel NS. (2021) Nat Rev Cancer 21: 669-680; Mukhopadhyay S, et al. (2021) Nat Cancer 2: 271-283). Interestingly, in the last decade, several independent authors reported that eIF4A activity is associated with translational adaptation particularly in the context of metabolic plasticity (Castelli LM, et al. (2011) Mol Biol Cell 22: 3379-3393; Tsokanos FF, et al. (2016) EMBO J 35: 1058-1076). Thus, it will be very informative to explore mechanistically the role of novel eIF4A inhibitors in regulating the cancer metabolism. [00325] One of the major limitations of the previously reported eIF4A inhibitors (Peters TL, et al. (2018) Clin Cancer Res 24: 4256-4270) was unintended cytotoxicity under cellular studies. Thus, to define the therapeutic window, the colony formation assays were performed using malignant DLBCL cells and non-malignant transformed lymphoblastoid (GMO cell lines) cells. Surprisingly, RBF197 has a therapeutic edge over the counterpart RBF208 by showing the least toxic effect on the GMO cell colonies while inhibiting DLBCL colonies in a dose-dependent manner. [00326] In silico analysis indicated the presence of a crucial hydrogen bond between the GLN195 of eIF4A1:RNA complex and the phenol moiety protonated, in this case, phenoxide moiety of the most active hit scaffold RBF197 (FIG.16), which potentially explains its higher potency over the other hits. 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[00394] Mukhopadhyay S, et al. (2020) Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers. Cancer Res 80: 1630-1643. [00395] Zhan Y, et al. (2020) Understanding the roles of stress granule during chemotherapy for patients with malignant tumors. Am J Cancer Res 10: 2226-2241. [00396] Anderson P, Kedersha N, Ivanov P. (2015) Stress granules, P-bodies and cancer. Biochim Biophys Acta 1849: 861-870. [00397] Tauber D, et al. (2020) Modulation of RNA Condensation by the DEAD-Box Protein eIF4A. Cell 180: 411-426 e416. [00398] Lacrima K, et al. (2007) Cyclin-dependent kinase inhibitor seliciclib shows in vitro activity in diffuse large B-cell lymphomas. Leuk Lymphoma 48: 158-167. [00399] Hu Y, et al. (2018) Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma. Leukemia 32: 2250-2262. [00400] Martinez-Reyes I, Chandel NS. (2021) Cancer metabolism: looking forward. Nat Rev Cancer 21: 669-680. [00401] Mukhopadhyay S, Vander Heiden MG, McCormick F. (2021) The Metabolic Landscape of RAS-Driven Cancers from biology to therapy. Nat Cancer 2: 271-283. [00402] Castelli LM, et al. (2011) Glucose depletion inhibits translation initiation via eIF4A loss and subsequent 48S preinitiation complex accumulation, while the pentose phosphate pathway is coordinately up-regulated. Mol Biol Cell 22: 3379-3393. [00403] Tsokanos FF, et al. (2016) eIF4A inactivates TORC1 in response to amino acid starvation. EMBO J 35: 1058-1076. [00404] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

CLAIMS What is claimed is: 1. A pharmaceutical composition comprising an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. The composition of claim 1, wherein R¹ is C1-C4 alkyl.

3. The composition of claim 1, wherein R¹ is methyl.

4. The composition of any one of claims 1 to 3, wherein R² is hydrogen.

5. The composition of any one of claims 1 to 3, wherein R² is C1-C4 alkyl.

6. The composition of any one of claims 1 to 3, wherein R² is methyl.

7. The composition any one of claims 1 to 6, wherein Ar¹ is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰.

8. The composition of any one of claims 1 to 6, wherein Ar¹ is phenyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰.

9. The composition of any one of claims 1 to 6, wherein Ar¹ is phenyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, methyl, methoxy, and ‒CO2H.

10. The composition of any one of claims 1 to 6, wherein Ar¹ is phenyl substituted with a ‒OH.

11. The composition of any one of claims 1 to 6, wherein Ar¹ is C5-C11 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰.

12. The composition of any one of claims 1 to 6, wherein Ar¹ is unsubstituted C5- C11 heteroaryl.

13. The composition of any one of claims 1 to 6, wherein Ar¹ is selected from thiophenyl, furanyl, and pyridinyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰.

14. The composition of any one of claims 1 to 6, wherein Ar¹ is selected from thiophenyl, furanyl, and pyridinyl, and is unsubstituted.

15. The composition of claim 1, wherein the compound has a structure represented by a formula:

, wherein R² is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof.

16. The composition of claim 1, wherein the compound has a structure represented by a formula:

, wherein each of R^20a, R^20b, R^20c, R^20d, and R^20e is independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰, or a pharmaceutically acceptable salt thereof.

17. The composition of claim 16, wherein R¹ is methyl.

18. The composition of claim 16 or claim 17, wherein each of R^20a, R^20b, R^20c, R^20d, and R^20e is independently selected from hydrogen and ‒OH.

19. The composition of claim 16 or claim 17, wherein R^20a is ‒OH.

20. The composition of claim 16, wherein the compound has a structure represented by a formula:

, or a pharmaceutically acceptable salt thereof.

21. The composition of claim 1, wherein the compound is selected from: ,

_,

,

or a pharmaceutically acceptable salt thereof.

22. The composition of claim 1, wherein the compound is selected from: ,

or a pharmaceutically acceptable salt thereof.

23. A method of modulating eIF4A1 activity in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein modulating is inhibiting.

25. The method of claim 23 or claim 24, wherein the cell is a cancer cell.

26. The method of any one of claims 23 to 25, wherein the cell is present in a tissue sample.

27. The method of claim 26, wherein the tissue sample is a malignant tissue sample.

28. The method of any one of claims 23 to 27, wherein the cell is human.

29. The method of any one of claims 23 to 28, wherein the cell has been isolated from a human prior to the contacting step.

30. The method of any one of claims 23 to 29, wherein contacting is via administration to a subject.

31. The method of claim 30, wherein the subject has been diagnosed with a need for modulation of eIF4A1 activity prior to the administering step.

32. The method of claim 30, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

33. A method of modulating eIF4A1 activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the subject is a mammal.

35. The method of claim 33, wherein the subject is a human.

36. The method of claim 33, wherein the subject has been diagnosed with a need for modulating eIF4A1 activity prior to the administering step.

37. The method of claim 33, wherein the subject has been diagnosed with a need for treatment of a disorder related to eIF4A1 activity prior to the administering step.

38. The method of claim 37, wherein the disorder is cancer.

39. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein the effective amount is a therapeutically effective amount.

41. The method of claim 39, wherein the effective amount is a prophylactically effective amount.

42. The method of claim 39, wherein the subject is a mammal.

43. The method of claim 42, wherein the mammal is a human.

44. The method of claim 39, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

45. The method of claim 39, further comprising the step of identifying a subject in need of treatment of cancer.

46. The method of any one of claims 39 to 45, wherein the cancer is a primary or secondary tumor.

47. The method of claim 46, wherein the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.

48. The method of any one of claims 39 to 45, wherein the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).

49. The method of any one of claims 39 to 48, wherein administering is oral or parental administration.

50. The method of claim 50, wherein the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.

51. The method of any one of claims 39 to 50, further comprising administering a therapeutically effective amount of an anti-cancer agent or radiotherapy to the subject.

52. The method of claim 51, wherein the anti-cancer agent or radiotherapy is administered prior to administration of the compound.

53. The method of claim 51, wherein the anti-cancer agent or radiotherapy is administered subsequent to administration of the compound.

54. The method of claim 51, wherein the anti-cancer agent is doxorubicin, cisplatin, 5-fluorouracin (5-FU), etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, or oxaliplatin.

55. A kit comprising a compound having a structure represented by a formula:

, wherein each of R¹ and R² is independently selected from hydrogen and C1-C4 alkyl; wherein Ar¹ is selected from C6-C12 aryl and C5-C11 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO₂R¹⁰; and wherein R¹⁰, when present, is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

56. The kit of claim 55, wherein the anti-cancer agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a DNA damage-inducing agent, and a mTor inhibitor agent.

57. The kit of claim 56, wherein the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

58. The kit of claim 56, wherein the antimetabolite agent is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

59. The kit of claim 56, wherein the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

60. The kit of claim 56, wherein the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

61. The kit of claim 56, wherein the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt thereof.

62. The kit of claim 56, wherein the DNA damage-inducing agent is selected from doxorubicin, cisplatin, 5-Fluorouracin, etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, oxaliplatin, or ionizing radiation.

63. The kit of claim 55, wherein the compound and the anti-cancer agent are co- packaged.

64. The kit of claim 55, wherein the compound and the anti-cancer agent are co- formulated.

65. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from: ,

,

, , ,

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

66. A method of modulating eIF4A1 activity in a cell, the method comprising contacting the cell with an effective amount of a compound selected from: ,

,

_,

,

or a pharmaceutically acceptable salt thereof.

67. A method of modulating eIF4A1 activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:

,

_,

,

^,

or a pharmaceutically acceptable salt thereof.

68. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from: ,

,

_,

,

or a pharmaceutically acceptable salt thereof.

69. A kit comprising a compound selected from:

,

_,

,

^,

or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.