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WO2025212165A1 - Chimères ciblant une protéolyse hétérobifonctionnelle à petites molécules ciblée - Google Patents

Chimères ciblant une protéolyse hétérobifonctionnelle à petites molécules ciblée

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Publication number
WO2025212165A1
WO2025212165A1 PCT/US2025/014620 US2025014620W WO2025212165A1 WO 2025212165 A1 WO2025212165 A1 WO 2025212165A1 US 2025014620 W US2025014620 W US 2025014620W WO 2025212165 A1 WO2025212165 A1 WO 2025212165A1
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Prior art keywords
cancer
compound
salt
map3k1
disease
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English (en)
Inventor
Amarnath Natarajan
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University of Nebraska Lincoln
University of Nebraska System
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University of Nebraska Lincoln
University of Nebraska System
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • MAP3K1 is an upstream kinase that phosphorylates IKKp and inhibition of MAP3K1 results in reduced p- I KKp levels, reduced tumor growth and metastasis in Kras mutation driven pancreatic cancer.(3,31 ,32) Analyses of MAP3K1 transcript levels in PC patients shows that higher MAP3K1 is associated with poorer 5-year survival (FIG.
  • FIG. 1 A Since drugs target the corresponding proteins, in FIG. 1 B the transcript and the protein levels of MAP3K1 were compared. Pearson and spearman values suggest that MAP3K1 protein levels correlate with the MAP3K1 transcript levels, making MAP3K1 protein an attractive target.
  • the present disclosure provides compounds, and pharmaceutically acceptable salts thereof, having the structure of X’-Y1’-ZT, wherein X’ is a MAP3K1 warhead moiety, Y’ is a linker moiety (“L”), and Z’ is an E3 ligase binding moiety (“E”).
  • X’ is a MAP3K1 warhead moiety
  • Y’ is a linker moiety (“L”)
  • Z’ is an E3 ligase binding moiety (“E”).
  • the MAP3K1 warhead moiety binds to MAP3K1 (for example, the MAP3K1 warhead moiety may be a quinoxaline-based small molecule fragment).
  • the E3 ligase binding moiety is a small molecule, a peptide, an antibody, or a fragment thereof (for example, the E3 ligase binding moiety may be a thalidomide analog).
  • the present disclosure provides compounds, and pharmaceutically acceptable salts thereof, having a structure of Formula 0: (0), wherein X is O, NR N , or S; Y and Z are each independently O, NR N , O, S, or CH2; each R N is independently H or C1-3 alkyl; R 1 and R 2 are each independently H or 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from O, S, and N, and the heteroaryl is optionally substituted with 1-4 R 3 ; each R 3 is independently halogen, Ci ⁇ alkyl, or Ce-w aryl, wherein each Ci-6 alkyl and Cg-io aryl is optionally substituted with 1-3 R 4 ; each R 4 is independently halogen, OH,CN, C1.6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, CO2H, or CO2C1.6 alkyl; ring A is C6-10 aryl, 5-7 membered heteroary
  • MAP3K1 signaling comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt disclosed herein.
  • methods of treating or preventing a disease or disorder capable of being modulated by MAP3K1 signaling inhibition comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt disclosed herein.
  • the disease or disorder capable of being modulated by MAP3K1 signaling inhibition is cancer.
  • FIGs. 1 A and 1 B show characteristics of MAP3K1 expression.
  • FIG. 1 A shows a Kaplan-Meier plot of
  • FIG. 1B shows a correlation plot between MAP3K1 expression and MAP3K1 protein levels.
  • FIG. 2 shows the domain architecture of MAP3K1 along with the binding sites of MAPK signaling molecules
  • the K1272M and C443A are inactivating mutations of the kinase and E3 ligase domains, respectively.
  • D878 is a caspase cleavage site.
  • K1371 is a feedback auto-ubiquitination site.
  • FIGs. 3A-3F show the results of efficacy studies with IKAM-1 in animal models of pancreatic cancer.
  • FIG. 4 shows the binding mode of IKAM-1 and Sorafenib in MAP3K1 generated using Schrodinger GLIDE.
  • MAP3K1 is shown as a cartoon with the ATP binding site shown in surface rendering. Sorafenib and IKAM-1 are shown as sticks.
  • the cells were incubated for 72 h and the cell growth were assessed using Presto Blue assay.
  • FIGs. 7A-7E show the results of follow up studies in colorectal cancer cells and colon tumor organoids.
  • FIG. 7A Western blot with HCT116 wild type (WT) and HCT116 CRBN(-/-) (generated by the UNMC CRISPR core) cell lysates showing CRISPR mediated CRBN knock out.
  • FIG. 7C Chemical structures of 50-008 and the control compound 50-074 (also called 17).
  • FIG. 7A Western blot with HCT116 wild type (WT) and HCT116 CRBN(-/-) (generated by the UNMC CRISPR core) cell lysates showing CRISPR mediated CRBN knock out.
  • FIG. 7B A 3-day growth inhibition dose response assay with HCT116 WT and HCT116 CRBN(-/-) cells subjected
  • FIGs. 9A and 9B show predictive modeling with 50-008 viability and available cell line proteomics data.
  • FIG. 9A Histogram of 50-008 IC50 values in the panel of 869 cancer cell lines.
  • FIG. 9B Predictive modeling using available cell line proteomics data.
  • FIGs. 10A-10C show the results of mechanism of action studies with 50-008.
  • FIG. 10B Dose-response studies with 50-008 in T47D cells, the IC50 value (0.56 nM) was derived through curve fitting using Sigmoidal 4 parameter logistic cure using Graph pad Prism 9.4.
  • FIG. 10B Dose-response studies with 50-008 in T47D cells, the IC50 value (0.56 nM) was derived through curve fitting using Sigmoidal 4 parameter logistic
  • T47D (4 x 104 cells/well) were subjected to 0.1 pM of 50-008 or 0.1 pM of bortezomib and monitored for the induction of apoptosis (pSIVA-IANBD, Kinetic apoptosis kit, Abeam) every 2h by live cell imaging (Incucyte®).
  • FIGs. 11 A and 11B show the effect of 50-008 on MAP3K1 mediated signaling.
  • FIG. 11A oncogenic signaling pathways regulated by MAP3K1.
  • FIG. 11 B T47D cells were treated with 0.1 pM of 50-008 for 12h and the resulting lysates were subjected Western blot analyses and probed with the indicated antibodies.
  • FIGs. 12A and 12B show histograms summarizing the IC50 values of 50-008 and FIG. 12A: Trametinib and FIG. 12B: Dabrafenib in large panels of cancer cell lines.
  • FIG. 13C Dose-response curves that reflect the efficacy of 50-008 (circles), T rametinib (squares) and Dabrafenib (diamonds) in COLO783 cells (skin cancer).
  • FIG. 13D Dose-response curves that reflect the efficacy of 50-008 (circles), Trametinib (squares) and Dabrafenib (diamonds) in A673 cells (bone cancer).
  • FIGs. 14A-14C show the results of PK studies with 50-008.
  • FIG. 14A Standard curve from the study
  • FIG. 14C Summary ofthe PK parameters estimated by non-compartmental model using WinNonlin 8.3.
  • FIG. 15 shows lung, breast and pancreas cancer cell lines that are most sensitive to 50-008 (IC50 ⁇ 10 nM).
  • FIG. 16 shows linkers for exploring efficacy as a function of conformational flexibility.
  • FIG. 17 shows a schema for a dose-escalating toxicity study.
  • FIG. 18 shows a 3-day growth inhibition dose response assay in HCT116 WT, HCT116 MAP3K1-KO and HCT116 CRBN-KO cells.
  • FIG. 20D 50-008 mediated degradation of MAP3K1 is blocked in a competitive inhibition setting with the MAP3K1 inhibitor 51 -106 or CRBN binder pomalidomide (Pom).
  • FIG. 20E a loss of MAP3K1 degradation was observed in a combination treatment setting with MLN492, a neddylation inhibitor that blocks the formation of a stable ternary complex between MAP3K1:50-008:CRBN.
  • FIG. 20F 50-008 was observed to mediate proteasomal degradation of MAP3K1.
  • MAP3K1 also constitutively associates with non-MAPK signaling molecules such as the cullin-RING ligase (CRL) 4 to regulate DNA-damage response and tubulin to regulate cell migration.
  • CTL cullin-RING ligase
  • perturbing MAP3K1 using selective small molecules is believed to impact not just MAP3K1 but the associated proteins as well, thus making MAP3K1 an attractive therapeutic target.
  • compounds and pharmaceutically acceptable salts thereof having the structure of Formula lb or Ic me cases, the compound or salt has the structure of Formula lb. In some cases, the compound or salt has the structure of Formula lb.
  • B is a 4- to 6-membered nitrogen-containing heterocycloalkyl. In some cases, B is a 4- membered nitrogen-containing heterocycloalkyl. In some cases, B is a 5-membered nitrogen-containing heterocycloalkyl. In some cases, B is a 6-membered nitrogen-containing heterocycloalkyl. In some cases, B has the , , . In some cases, B has the structure
  • L is C2-10 alkylene, C2-10 alkenylene, or C2-10 polyalkoxy, each optionally interrupted by one NHC(O)CH 2 , C(O), orcyclopropanyl.
  • L is C2-10 alkylene, C2-10 alkenylene, or Cwo polyalkoxy.
  • L is C2.10 alkylene or C2-10 polyalkoxy.
  • L is C2.10 alkylene.
  • L is C2-10 polyalkoxy.
  • L is interrupted by one NHC(O)CH2, C(O), or cyclopropanyl.
  • L is interrupted by one NHC(O)CH 2 .
  • L is interrupted by one C(O).
  • L is
  • L is . In some cases, L is . In some cases, L is . In some cases, L is . In some cases, L is . In some cases, L is . In some cases, L is
  • Specifically contemplated compounds of the disclosed Formula I include the compounds having a structure shown in Table 1. Table 1
  • the compound is compound 50-008 or a pharmaceutically acceptable salt thereof.
  • the compound is selected from Compound 50-008, Compound 58-136, Compound 58-140, Compound 58- 145, and Compound 58-149, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound 50-008, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound 58- 136, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound 58-140, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound 58-145, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound 58-149, or a pharmaceutically acceptable salt thereof.
  • alkyl refers to straight chained and branched saturated hydrocarbon groups containing one to thirty carbon atoms.
  • C n means the alkyl group has “n” carbon atoms.
  • C4 alkyl refers to an alkyl group that has 4 carbon atoms.
  • Cre alkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (e.g., 1 to 6 carbon atoms), as well as all subgroups (e.g., 1-5, 2-6, 1-4, 3-6, 1, 2, 3, 4, 5, and 6 carbon atoms).
  • alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), f-butyl (1,1 -dimethylethyl), and hexyl.
  • an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.
  • alkylene refers to an alkyl group that is substituted with at least two nonhydrogen substituents (i.e., is at least disubstituted).
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms. Specifically contemplated is an alkenyl group with one or more fluorine atoms, e.g., trifluoromethyl. The alkenyl group can be perhalogenated.
  • halogen refers to heteroatoms selected from F, Cl, Br, and I.
  • alkenyl is defined identically as “alkyl” except for containing at least one carboncarbon double bond, and having two to thirty carbon atoms.
  • C n means the alkenyl group has “n” carbon atoms.
  • C4 alkenyl refers to an alkenyl group that has 4 carbon atoms.
  • C2-6 alkenyl refers to an alkenyl group having a number of carbon atoms encompassing the entire range (e.g., 2 to 6 carbon atoms), as well as all subgroups (e.g., 2-5, 2-4, 3-6, 2, 3, 4, 5, and 6 carbon atoms).
  • alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl, and butenyl. Unless otherwise indicated, an alkenyl group can be an unsubstituted alkenyl group or a substituted alkenyl group.
  • alkenylene refers to an alkenyl group that is substituted with at least two nonhydrogen substituents (i.e., is at least disubstituted).
  • haloalkenyl refers to an alkenyl group substituted with one or more halogen atoms. Specifically contemplated is an alkenyl group with one or more fluorine atoms. The alkenyl group can be perhalogenated.
  • alkynyl is defined identically as “alkyl” except for containing at least one carboncarbon triple bond, and having two to six carbon atoms.
  • C n means the alkynyl group has “n” carbon atoms.
  • C4 alkynyl refers to an alkynyl group that has 4 carbon atoms.
  • C2-6 alkynyl refers to an alkynyl group having a number of carbon atoms encompassing the entire range (e.g., 2 to 6 carbon atoms), as well as all subgroups (e.g., 2-5, 2-4, 3-6, 2, 3, 4, 5, and 6 carbon atoms).
  • alkynyl groups include ethynyl, 1 -propynyl, 2-propynyl, and butynyl. Unless otherwise indicated, an alkynyl group can be an unsubstituted alkenyl group or a substituted alkenyl group.
  • haloalkynyl refers to an alkynyl group substituted with one or more halogen atoms. Specifically contemplated is an alkynyl group with one or more fluorine atoms. The alkynyl group can be perhalogenated.
  • heteroaryl refers to a cyclic aromatic ring having five to seven total ring atoms (e.g., a monocyclic aromatic ring with 5-7 total ring atoms), and containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the aromatic ring.
  • a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one to four, substituents as described herein.
  • the heteroaryl group is substituted with one or more alkyl groups, such as methyl groups.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, pyrrolyl, pyrazolyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.
  • heterocycloalkyl refers to a non-aromatic monocyclic, fused, spiro or bridged ring system which can be saturated or contain one or more units of unsaturation, having five to eight ring atoms in which one to four (e.g., one to four, or one, two, three, or four) ring atoms is a heteroatom selected from, N, S, and O.
  • heterocycles include, but are not limited to, quinuclidinyl, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino (including, for example, 3-morpholino, 4-morpholino), 2- thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1 -pyrrolidinyl, 2-pyrrolidinyl,
  • terapéuticaally effective amount refers to an amount of a compound sufficient to treat, ameliorate, or prevent the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect.
  • the effect can be detected by, for example, an improvement in clinical condition, reduction in symptoms, or by any of the assays or clinical diagnostic tests described herein or known in the art.
  • the precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 can be administered, per dose, in an amount of about 0.005, 0.05, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or750 milligrams, including all doses between 0.005 and 750 milligrams.
  • the compounds described herein may be formulated in pharmaceutical compositions with a pharmaceutically acceptable excipient, carrier, or diluent.
  • the compound or composition comprising the compound is administered by any route that permits treatment of the disease or condition.
  • One route of administration is oral administration.
  • the compound or composition comprising the compound may be delivered to a patient using any standard route of administration, including parenterally, such as intravenously, intraperitoneally, intrapulmonary, subcutaneously or intramuscularly, intrathecally, topically, transdermally, rectally, orally, nasally or by inhalation.
  • Slow release formulations may also be prepared from the agents described herein in order to achieve a controlled release of the active agent in contact with the body fluids in the gastro intestinal tract, and to provide a substantial constant and effective level of the active agent in the blood plasma.
  • the crystal form may be embedded for this purpose in a polymer matrix of a biological degradable polymer, a water-soluble polymer or a mixture of both, and optionally suitable surfactants. Embedding can mean in this context the incorporation of micro-particles in a matrix of polymers. Controlled release formulations are also obtained through encapsulation of dispersed microparticles or emulsified micro-droplets via known dispersion or emulsion coating technologies.
  • Formulations e.g., for parenteral or oral administration, are most typically solids, liquid solutions, emulsions or suspensions, while inhalable formulations for pulmonary administration are generally liquids or powders.
  • a pharmaceutical composition can also be formulated as a lyophilized solid that is reconstituted with a physiologically compatible solvent prior to administration.
  • Alternative pharmaceutical compositions may be formulated as syrups, creams, ointments, tablets, and the like.
  • pharmaceutically acceptable excipient refers to an excipient for administration of a pharmaceutical agent, such as the compounds described herein.
  • the term refers to any pharmaceutical excipient that may be administered without undue toxicity.
  • Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles.
  • Other exemplary excipients include antioxidants (e.g., ascorbic acid), chelating agents (e.g., EDTA), carbohydrates (e.g., dextrin, hydroxyalkylcellulose, and/or hydroxyalkylmethylcellulose), stearic acid, liquids (e.g., oils, water, saline, glycerol and/or ethanol) wetting or emulsifying agents, pH buffering substances, and the like.
  • Liposomes are also included within the definition of pharmaceutically acceptable excipients.
  • compositions described herein are formulated in any form suitable for an intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • compositions particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • disintegrating agents such as cross-linked povidone, maize starch, or alginic acid
  • binding agents such as povidone, starch, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inflammatory diseases include but are not limited to arthritis, atherosclerosis, inflammatory bowel disease, rheumatoid arthritis, colitis, pancreatitis, hepatitis, thyroiditis, Crohn’s disease, asthma, and pelvic inflammatory disease.
  • neurological disorders and diseases include but are not limited to Alzheimer’s disease, Parkinson's disease, traumatic brain injury, stroke, Amyotrophic Lateral Sclerosis, Huntington’s disease, ischemia, attention deficit disorders, and epilepsy.
  • Specific cancers contemplated include pancreatic cancer, lymphoma, leukemia, colon cancer, colorectal cancer, familial adenomatous polyposis (FAP), hereditary non-polyposis cancer (HNPCC), colitis-associated cancer, gastric cancer, and breast cancer.
  • Specific inflammatory diseases contemplated include arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, chronic inflammatory demyelinating polyradiculoneuritis, asthma, inflammatory bowel disease, helicobacter pylori-associated gastritis, Crohn’s disease, ulcerative colitis, and systemic inflammatory response syndrome.
  • Autoimmunity as the actual cause of human illness (rather than a consequence or harmless accompaniment) can be used to establish criteria that define a disease as an autoimmune disease.
  • Autoimmune diseases or diseases which are characterized as involving immune dysfunction or disregulation include systemic lupus erythematosis (SLE), diabetes mellitus (type I), asthma, ulcerative cholitis, Grave's disease, arthritis, including rheumatoid arthritis and osteoarthritis, pernicious anemia, and multiple sclerosis, among numerous others.
  • autoimmune diseases may be treated using the method of the present disclosure including autoimmune blood diseases, including pernicious anemia, autoimmune hemolytic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, ankylosing spondilitis; autoimmune diseases of the musculature including polymyositis and dermatomyositis, autoimmune diseases of the ear including autoimmune hearing loss and Meniere's syndrome, autoimmune eye diseases, including Mooren's disease, Reiter's syndrome and Vogt-Koyanagi-Harada disease, autoimmune diseases of the kidney including glomerulonephritis and IgA nephropathy; diabetes mellitus (type I); autoimmune skin diseases including pemphigus (autoimmune bullous diseases), such as pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, bullous pemphigoid, vitiligo, epidermolysis bullosa acquisit
  • a compound disclosed herein i.e., a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 , and pharmaceutically acceptable salts thereof.
  • the cancer is skin cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, brain cancer, kidney cancer, lung cancer, leukemia, lymphoma, multiple myeloma, thyroid cancer, bone cancer, esophageal cancer, or pancreatic cancer.
  • kits comprising a compound disclosed herein (i.e., a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 , and pharmaceutically acceptable salts thereof) and, optionally, a second therapeutic agent useful in the treatment of diseases and conditions wherein inhibition of IKK£ provides a benefit, packaged separately or together, and an insert having instructions for using these active agents.
  • Example reagents and conditions for reactions of Scheme 1 are: (i) Acetic acid, cone. HNO3, rt, 24 h; (ii) PCI5, POCI3, reflux; (iii) heteroarylborane or heteroarylborate, Pd(PPh3)4, aqueous Na2CO3, DMF:Dioxane (1 :1), 100° C; (iv) Pt/C, H2, EtOH, room temperature; (v) BTC, toluene, reflux; (vi) NaOH, MeOH:THF (1:1), 50 °C, 16h. Further derivatization with an amine-bearing E3-ligase binding moiety-Linker moiety conjugate (E-L-NH2) yields compounds of Formula (I).
  • Compounds as disclosed herein can be prepared by the method noted in the above scheme.
  • 50-008 reduced p-l KK and p-ERK, but not p-Akt levels.
  • 50-008 exhibited comparable potencies to FDA approved MEK (Trametinib) and BRAF (Dabrafenib) inhibitors.
  • Preliminary pharmacokinetic (PK) studies revealed that intraperitoneal administration (30 mg/kg) of 50-008 resulted in a 62% bioavailability, which as comparable to IKAM- 1.(3) It is thought that 50-008 perturbs MAP3K1 associated signaling to inhibit cancer cell growth.
  • a quinoxaline analog is conjugated to thalidomide (TH) that binds to CRBN through a flexible linker.
  • TH thalidomide
  • the instant examples investigate linker rigidity between QA and TH to improve membrane permeability and bioavailability, by reducing exposed polar surfaces and lowering entropic penalty, respectively.(20,21)
  • These analogs provide structural information regarding the binding mode, mechanism of action and efficacy as a function of linker conformation.
  • the analogs with IC50 ⁇ 29 nM in Q20-70T are subjected to PRISM screen followed by solubility, metabolic stability, permeability, and PK studies.
  • a 3+3 dose-escalation toxicity study is conducted to determine the optimal dose of 50-008 and an improved analog for PD studies.(22,23) Changes in body weight, CBC, CMP, TNFa and IL-6 are used to assess toxicity. Since 3/10 highly sensitive cell lines (IC50 ⁇ 10 nM) in Aim 1 carry a PI3K3CA mutation, 50-008 and/or analogs are evaluated in both a Kras mutation and PI3K3CA mutation driven tumor models. These studies lay the foundation for investigation new drug (IND) enabling toxicity studies Example 1 : Preliminary MAP3K1 Inhibition Studies
  • Map3k1 null mice are viable and exhibit normal phenotype.
  • Transforming growth factor (TGF) a in the advancing eyelid tip facilitate the migration of epithelial cells to cover the cornea. Consistently, deletion of TGFa leads to mice born with open eyes, suggesting defective cell migration as the cause of eyelid closure in Map3k1 null mice.
  • Single cell tracking studies with Map3k1-'- mouse embryo fibroblasts (MEFs) confirmed defective motility. Since the Map3k1 null mice are normal except for the eyelid closure defect, most migratory processes during embryonic development are compensated for in Map3k1 null mice.(38)
  • Map3k1 DKD Map3k1 DKD
  • Map3k1 kinase domain KD
  • bacterial LacZ gene which expressed a MAP3K1-0-galactosidase fusion protein.
  • Map3k1 + mice Map3 f DKD ® KD were normal except the failure of eyelid closure, while MAP3K1 +/DKD exhibited normal development including closed eyelids at birth.
  • Map3k1 +IDKD and Map3 1 DKD/DKD revealed that Map3k1 specifically transduces signals from TGF- / activin receptors, but not from TGFa, to JNK to regulate F-actin mediated epidermal keratinocyte migration but not fibroblasts.
  • IKAM-1 as a selective MAP3K1 inhibitor- In vitro kinase assays and cell-based kinase assays (KiNativ)
  • in vitro kinase assays are routinely used to guide SAR, it is increasingly acknowledged that the correlation between the activity I selectivity exhibited by an inhibitor in the in vitro kinase assays and cell-based kinase assays are poor.
  • profiling the FDA approved kinase inhibitor, Sorafenib in an in vitro kinase assay identified 65 kinases with sub-jiM potency and 6 (DDR1 , HIPK4, FLT3 K663Q , MLTK, DDR2 and RET M918T ) of these 65 kinases exhibited single digit nM activities.
  • the KiNativ screen preferentially profiles kinases in the their active states.(45)
  • the structural similarity between Sorafenib and IKAM-1 suggests that both Sorafenib and IKAM-1 target activated full length MAP3K1 which is not recapitulated in the in vitro setting.
  • IKAM-1 and Sorafenib in cell-free and cell-based kinase profiling studies.
  • the effect of IKAM-1 on the kinase activities were measured in the in vitro kinase assays.
  • the in vitro kinase assays with Sorafenib measured binding affinity.
  • the IKAM-1 KiNativ screen was conducted with PANC1 lysates while the Sorafenib KiNativ screen was conducted with A375 lysates.
  • IKAM-1 inhibits pancreatic tumor growth and metastasis:
  • mice were treated orally with either IKAM-1 (40 mg/kg) or vehicle.
  • IKAM-1 treated mice reduced tumor volume and tumor weight was observed (FIGs. 3A and 3B) when compared to vehicle treated mice.
  • Reduced expression of p-IKKp in the IKAM-1 treated tumors was observed when compared to vehicle treated tumors (FIGs. 3C and 3D) indicating in vivo target perturbation.
  • IKAM-1 The efficacy of IKAM-1 in an immunocompetent syngeneic orthotopic model was also assessed.
  • C57BL/6 mice were orthotopically challenged with KrasG12D/Trp53R172H/Pdx1Cre (KPC1245) tumor cells (5 x 10 4 ) derived from a primary culture of spontaneously generated murine KPC tumor. 6 days post challenge, treatment cohorts began receiving daily oral administration of IKAM-1 (40 mg/kg) for four weeks.
  • IKAM-1 was formulated as previously described, (46) and 100 pL of IKAM-1 solution was dosed daily by oral gavage.
  • mice were treated with gemcitabine at 100 mg/kg every 4 days by Intraperitoneal administration.
  • mice Animal necropsies were generally unremarkable, with the exception of periodic gastric gas accumulation, IKAM-1 treated mice showed no apparent signs of toxicity.
  • the final tumor volumes and weights from mice from the various groups are summarized in FIGs. 3E and 3F. These results demonstrate that IKAM-1 does not exhibit any adverse effect in pancreatic tumor bearing mice with an intact immune system. Together, these results show that oral dosing of IKAM-1 reduced p-IKKD levels in tumors, reduced PC tumor growth and metastasis with no obvious toxicities.(3)
  • PROTACs vs. Inhibitors
  • SMIs small molecule inhibitors
  • POI protein of interest
  • the productive formation of a ternary complex in which the PROTAC is sandwiched by the POI and the E3-ligase allows the E3-ligase to polyubiquitinate the POI (event driven model).
  • the ubiquitinated POI is then recognized by the cellular ubiquitin proteosome machinery resulting in the proteolysis of the POI.(18)
  • the chemically induced degradation of the POI results in the release of the PROTAC and E3-ligase to initiate the next iteration of binding- ubiquitination-proteolysis of the POI.(13)
  • the catalytic nature of the PROTAC mediated degradation alleviates the need for high drug concentrations.
  • IKAM-1 binding mode shows that the F-atom is solvent exposed. Therefore, the F-atom was replaced with a -CO2H in 2 to generate 3, which was conjugated to a set of 14 linkers with varied length and composition (Compounds 50-001, 50-002, 50-003, 50-005, 50-006, 50-007, 50-009, 50-010, 50-011, 50-012, 50-013, 50-014, and 50-025).
  • PROTACs were generated by conjugating the above analogs to cereblon (CRBN) binding IMiDs (Scheme 2 and FIG. 6).
  • Compound 48-069 has the structure:
  • HCT116 WT cells were subjected to 1 .M each of 50-008 and 50-074, and HCT 116 CRBN(-/-) cells were subjected to 1 jiM of 50-008.
  • FIG. 8A S-phase arrest was observed only in HCT 116 WT cells and not in either 50-074 treated HCT116 cells or 50-008 treated HCT 116 CRBN(-/-) cells (FIG. 8A).
  • a follow up dose-response study with 50-008 in HCT116 WT cells (FIG.
  • a large-scale PRISM cancer cell viability profiling was conducted using DNA bar-coded cells.(19) Briefly, cells were treated with increasing concentration of 50-008 (5 nM - 10 j M) and incubated for 5-days. The cells were then lysed the mRNA isolated, and the barcode sequences were amplified by PCR and detected by a Luminex scanner. The amount of barcode correlates with the viability of the cells following treatment. This was used to generate cell line sensitivity signature for 50-008. Although 930 cancer cell lines were screened only 869 passed quality control (QC).
  • QC quality control
  • Correlation plots are generated for the > 6300 proteins that were quantified and the IC50 values of 50-008. There is a large set (> 265 cancer cell lines) of cell lines that are sensitive to 50-008, so predictive modeling leads to additional testable hypotheses that impact various cancer types.
  • One of the 14 highly sensitive cell lines is the luminal A breast cancer cell line T47D.
  • MAP3K1 mediated downstream signaling also relies on the composition of the MAP3K1 associated proteins.
  • association of MAP3K1 with RAD51AP1 activates HER2 mediated PI3K/Akt pathway
  • association of MAP3K1 with the RAD51AP1-DYRK4 fusion protein which is found in 9% of luminal breast cancer, rewires the signaling through the MEK-ERK pathway.
  • BAALC brain and acute leukemia, cytoplasmic
  • BAALC-MAP3K1 results in activation of ERK to support proliferation.
  • ERK associates with MAP3K1 and p-ERK is a key driver of oncogenesis.
  • 50-008 treatment results in reduced p-ERK levels and as a consequence reduced DUSP4 levels resulting in increased p-JNK and c-Jun.
  • a CRISPR paralog screen identified DUSP4/6 supports the growth of NRAS and BRAF mutant cells.
  • Reduction in p-ERK and DUSP4 observed with 50-008 treatment phenocopies the effects associated with BRAF and MEK inhibition, which is a therapeutic strategy for KRAS mut driven cancers.
  • the efficacy of 50-008 was compared against the FDA approved MEK and BRAF inhibitors, Trametinib and Dabrafenib, respectively (FIGs. 12A and 12B).
  • Scheme 4 summarizes a representative synthesis of PROTACs with constrained linkers.
  • Ring B is a nitrogen-containing heterocyclic ring having 3 to 8 total ring members.
  • a suitable nitrogen-containing heterocyclic compound b having a linker L as defined herein is coupled with starting compound a to yield an intermediate compound c.
  • This intermediate compound c is deprotected, then further coupled with compound 51-115 to yield a PROTAC with a constrained linker having a structure of Formula lb.
  • Compound 50-008 was found to inhibit both T47D and MCF7 cell lines using methods known in the art and disclosed herein (see e.g., Rana S. et al. Bioorg Med Chem Lett. 2019 Jun 1 ;29(11):1375-1379). Data are presented in FIGs. 20A-20F.

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Abstract

L'invention concerne des composés présentant une structure de formule 0, de formule I, de formule la, de formule lb, de formule Ic, ou de tableau 1 tels que divulgués dans la présente invention, et des procédés d'utilisation des composés divulgués pour inhiber l'activité MAP3K1. Par exemple, les composés de formule 0, de formule I, de formule la, de formule lb, de formule Ic ou de tableau 1 tels que divulgués dans la présente invention sont utiles pour des méthodes de traitement de maladies et de troubles comprenant, sans caractère limitatif, le cancer.
PCT/US2025/014620 2024-04-05 2025-02-05 Chimères ciblant une protéolyse hétérobifonctionnelle à petites molécules ciblée Pending WO2025212165A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210002296A1 (en) * 2018-01-12 2021-01-07 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US20230043970A1 (en) * 2016-08-15 2023-02-09 Neupharma, Inc Certain chemical entities, compositions, and methods
WO2023066350A1 (fr) * 2021-10-22 2023-04-27 标新生物医药科技(上海)有限公司 Composé ligand de ligase e3 crbn, agent de dégradation de protéine développé sur la base d'un composé de ligand, et leurs utilisations
US20230250085A1 (en) * 2017-12-01 2023-08-10 Board Of Regents Of The University Of Nebraska Quinoxaline compounds and uses thereof

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Publication number Priority date Publication date Assignee Title
US20230043970A1 (en) * 2016-08-15 2023-02-09 Neupharma, Inc Certain chemical entities, compositions, and methods
US20230250085A1 (en) * 2017-12-01 2023-08-10 Board Of Regents Of The University Of Nebraska Quinoxaline compounds and uses thereof
US20210002296A1 (en) * 2018-01-12 2021-01-07 Kymera Therapeutics, Inc. Protein degraders and uses thereof
WO2023066350A1 (fr) * 2021-10-22 2023-04-27 标新生物医药科技(上海)有限公司 Composé ligand de ligase e3 crbn, agent de dégradation de protéine développé sur la base d'un composé de ligand, et leurs utilisations

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WEN LONG-PING, ZHU YANGYANG, ZHONG SUQIN, YANG YINYIN, WU YU, WANG LIANSHENG, LI SHANSHAN, BIAN ZHEN-HUA, ZHANG JIQIAN, WEI PENGFE: "Enhancement of ubiquitination-dependent mitophagy by unconventionally-acting PROTACs", RESEARCH SQUARE, 19 March 2024 (2024-03-19), pages 1 - 52, XP093365842, Retrieved from the Internet <URL:https://assets-eu.researchsquare.com/files/rs-4130669/v1_covered_01def2f6-855b-45ea-9fd6-b3731bf5a2b8.pdf?c=1710946095> DOI: 10.21203/rs.3.rs-4130669/v1 *

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