TW201806592A - Methods for treating cancer - Google Patents

Abstract

Methods comprising administering and kits comprising a therapeutically effective amount of at least one first compound chosen from compounds having Formula A: and compounds having Formula B: prodrugs thereof, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing; and a therapeutically effective amount of at least one second compound chosen from compounds having Formula C: prodrugs thereof, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing.

Description

Ways to treat cancer

The disclosed herein is a method for treating cancer in an individual, comprising administering a therapeutically effective amount of at least one first compound selected from cancer stemness inhibitors, prodrugs, derivatives thereof, any of the foregoing A pharmaceutically acceptable salt of one, and a solvate of any of the foregoing; and a therapeutically effective amount of at least one second compound selected from the group consisting of kinase inhibitors, prodrugs, derivatives thereof, any of the foregoing A pharmaceutically acceptable salt thereof, and a solvate of any of the foregoing.

In some specific examples, the at least one first compound selected from cancer stemness inhibitors may be, for example, at least one compound selected from compounds of formula A:

Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing.

In some embodiments, the at least one first compound selected from cancer stemness inhibitors can be, for example, at least one compound selected from compounds of formula B:

Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing.

In certain embodiments, the at least one second compound selected from kinase inhibitors can be, for example, at least one compound selected from compounds of formula C:

Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing.

The National Cancer Institute estimates that 1,685,210 new cases of cancer will be diagnosed in the United States in 2016 and 595,690 people will die from the disease. The most common cancers are inferred to be breast cancer, lung and bronchial cancer, prostate cancer, colon and rectal cancer, bladder cancer, melanoma of the skin, non-Hodgkin's lymphoma, thyroid cancer, kidney and renal pelvis cancer, leukemia, endometrium Cancer, and pancreatic cancer. Despite advances in the treatment of certain forms of cancer through surgery, radiation therapy, and chemotherapy, many types of cancer are virtually incurable. Even when there is an effective treatment for a specific cancer, the side effects of such treatment may have a serious impact on the patient's quality of life Harmful effects.

Most conventional chemotherapeutic agents have toxicity and limited efficacy (especially for patients with advanced solid tumors). Conventional chemotherapeutic agents cause cytotoxicity to both healthy non-cancerous cells and cancerous cells. The therapeutic index of these chemotherapeutic compounds (ie, the measure of the ability of the treatment to distinguish cancerous cells from normal cells) may be quite low. Often, a dose of chemotherapeutic drugs effective in killing cancer cells will also kill normal cells, especially those normal cells that undergo frequent cell divisions (such as epithelial cells and bone marrow cells). When normal cells undergo chemotherapy, they often produce side effects (such as hair loss, suppression of hematopoiesis, which cause anemia and immune insufficiency, and nausea). Depending on the general health of the patient, such side effects may hinder the administration of the entire chemotherapy, or at least impose significant discomfort on the cancer patient to reduce their quality of life. Even for cancer patients who respond to chemotherapy and whose tumors have subsided, the cancer often recurs, progresses, and spreads by metastasis after the initial response to chemotherapy. Such recurring cancers are often highly refractory to other rounds of chemotherapeutic treatment.

Due to the chemical resistance of the disease, the toxicity characteristics of currently available systemic chemotherapeutic agents, and the general poor health of liver cancer (HCC) patients and potential liver dysfunction, advanced liver cancer remains a major clinical challenge. The sorafenib hepatocellular carcinoma evaluation protocol (SHARP) trial remains the only randomized controlled trial of systemic chemotherapeutic agents to demonstrate the statistically significant survival benefit of patients with advanced unresectable HCC. In this study, 602 patients were randomly assigned to receive sorafenib (400 mg twice daily) or placebo. Moderate overall survival (OS) of 10.7 months was observed in the treatment group, compared with 7.9 months in the placebo group. The time to tumor progression (TTP) in the sorafenib and placebo groups was 5.5 months and 2.8 months, respectively.

The benefits of sorafenib monotherapy are important, but not large. Many suffer Patients do not experience disease control, and disease control can be short-lived in patients receiving treatment to achieve disease control. Unfortunately, no other agents have proven to be more effective. Compared with sorafenib alone, other recent regimens (for example, FOLFOX, brivanib, sunitinib, and linifanib) have failed to confirm OS statistics Learning has improved significantly.

A number of combined treatment studies have also been conducted using sorafenib plus additional drugs or regimens. However, a small number of combinations have proven to be robust enough for further evaluation in the critical setting of Phase III. Those that have been evaluated in the Phase III trial, such as Brefani, FOLFOX, and Erlotinib, have failed to show the advantages of using sorafenib alone. In the BRISK-FL study, the toxicity was increased and the quality of life was poor, and in the combination study with 5-FU or 5-FU derivative therapy, an increased incidence of hand-foot syndrome was observed. There is a huge unmet medical need for active systemic treatment of HCC.

It is believed that cancer stem cells (CSC) or cancer cells with high stemness (highly stem cancer cells) are the cause of rapid tumor recurrence and resistance. It is believed that CSC has at least the following four characteristics:

1. Dryness

As used herein, stemness means the ability of stem cell populations to renew themselves and transform into cancer cells (Gupta PB et al., Nat. Med. 2009; 15 (9): 1010-1012). Although CSC only forms a small percentage of the entire cancer cell population in the tumor (Clarke MF, Biol. Blood Marrow Transplant. 2009; 11 (2 suppl 2): 14-16), it will cause differentiation of the main body of the tumor Differential mass spectrum of cancer cells (see Gupta et al. 2009). In addition, CSC has the ability to spread to other locations in the body (seeds where new tumors are grown) by metastasis (Jordan CT et al. N. Engl. J. Med. 2006; 355 (12) : 1253-1261).

2. Abnormal sending way

The dryness of CSC can also be linked to the disorder of the signaling pathway, which may contribute to its ability to transfer equally. In normal stem cells, the stem signaling pathway is tightly controlled and genetically complete. Conversely, the abnormal regulation of the stem signaling pathway in CSC plays a key role in the uncontrolled self-renewal of these cells and their transformation into cancer cells (see Ajani et al. Semin.Oncol. (2015) 42 Suppl. 1: S3-17). Dysregulation of dry signaling pathways also contributes to CSC's resistance to chemotherapy and radiation therapy and to cancer recurrence and metastasis. Exemplary dry signaling pathways involved in the induction and maintenance of dry characteristics in CSC include (but are not limited to) Janus kinase / transcribed signal transducers and activators (JAK / STAT), Hedgehog (Desert (DHH)) , Indian (IHH), and Sonic (SHH)) / PATCHED / (PTCH1) / SMOOTHENED (SMO), NOTCH / DELTA (DLL1, DLL3, DLL4) / JAGGED (JAG1, JAG2) / CSL (CBF1 / Su (H ) / Lag-1), WNT / APC / GSK3 / β-Chain / TCF4 and NANOG (Boman BM et al., J. Clin. Oncol. 2008; 26 (17): 2828-2838).

3. Resistance to traditional treatment

Unfortunately, cancers that initially responded to chemotherapy and radiation therapy often recur in the form of resistance to these traditional treatments. Although the detailed mechanisms that underlie such resistance have not been fully understood, CSC dry hair development in the context of the tumor microenvironment (Borovski T. et al. Cancer Res. 2011; 71 (3): 634-639) Abnormal regulation of information pathways (see Boman et al. 2008) may play a key role in gaining such resistance.

4. Ability to contribute to tumor recurrence and metastasis

Chemotherapy and radiation kill large rapidly dividing cancer cells in tumors Partly but not CSC, it survives by gaining resistance (see Jordan et al. 2006). Radiation / chemotherapy-resistant CSC can also gain the ability to transfer to different locations in the body and maintain dryness by interacting with the microenvironment at these locations, thereby allowing the spread of metastatic tumor growth (see Boman et al. 2008 ). Interestingly, this enhanced tumorigenicity of CSC is related to the expression of genes (such as cell surface markers such as CD44, CD133, and CD166) that would normally be expressed in adult stem cells.

Because the survival of CSC may be the primary reason why cancer recurs after chemotherapy and / or radiation therapy, anti-cancer treatment that specifically targets the abnormal signaling pathway of CSC may help prevent tumor metastasis and prevent cancer Patients with relapsed diseases that can no longer be treated with traditional treatments offer viable treatment options. Such a method can thus improve the survival and quality of life of cancer patients (especially those suffering from metastatic disease). Unlocking this unopened potential involves the identification and verification of the necessary pathways for CSC self-renewal and survival. Although many signaling pathways that regulate the proliferation and differentiation of embryonic or adult stem cells are known, it remains to be seen whether these same pathways are required for cancer stem cell self-renewal and survival.

Transcription factor transcription signal transducer and activator 3 (Signal Transducer and Activator of Transcription 3, also known as acute phase response factor (Acute-Phase Response Factor, APRF), DNA binding protein APRF, ADMIO3, HIES; referred to as STAT3 ) Is a STAT family of seven transcription factors (STAT1 to STAT6, including STAT5a and STAT5b). STAT is activated by receptor-linked tyrosine kinase (such as Janus kinase (JAK)) or by receptors with inherent tyrosine kinase activity (such as PDGFR, EGFR, FLT3, EGFR, ABL, KDR, c-MET , And or HER2) activation. After phosphorylation of tyrosine through receptor-linked kinase, the phosphorylated STAT protein ("pSTAT") dimerizes to form homodimers or heteromers Dimer, and translocated from the cytoplasm to the nucleus, where it combines with special DNA response elements in the promoter of the target gene and induces gene expression. STAT 2, 4, and 6 mainly regulate the immune response, while STAT3 and STAT1 and STAT5 regulate genes that control cell cycle (cyclin D1, D2, and c-MYC), and genes for cell survival (BCL-XL, BCL-2, MCL-1), expression of genes associated with angiogenesis (HIF1α, VEGF) (Furqan et al. Journal of Hematology & Oncology (2013) 6:90).

In normal cells, STAT3 activation is transient and tightly regulated, lasting, for example, about 30 minutes to several hours. However, in a variety of human cancers (not only including all major epithelial cancers but also some hematological tumors), it is found that the STAT3 line is abnormally active. Continuously active STAT3 occurs in more than half of all breast and lung cancers, as well as colorectal cancer (CRC), ovarian cancer, hepatocellular carcinoma, and multiple myeloma, and more than 95 in all head / neck cancers Occurred in%. STAT3 therefore seems to play an important role in cancer progression and may be one of the main mechanisms by which cancer cells acquire drug resistance. STAT3 is an effective transcription regulator that targets genes involved in cell cycle, cell survival, tumor formation, tumor invasion, and metastasis, including (but not limited to) BCL-XL, c-MYC, cyclin D1, VEGF, MMP -2, with SURVIVIN. STAT3 is also a key negative regulator of tumor immune surveillance and immune cell replenishment. Therefore, STAT3 may enable the survival and self-renewal of CSC in a broad spectrum of cancers. Pharmaceutical compounds with activity against CSC (eg, inhibition by STAT3) have great promise as treatment options for cancer patients with advanced disease.

In some specific examples, the at least one compound selected from compounds having Formula A may be, for example, a CSC growth and survival inhibitor. U.S. Patent No. 8,877,803 describes compounds having formula A, which is a cell ₅₀ of IC ~ 0.25μM inhibition of STAT3 pathway activity. Example 13 of the '803 patent provides an exemplary method of synthesizing at least one compound of Formula A. In certain specific examples, the at least one compound selected from compounds having formula A can be used, for example, for methods for treating cancer. In Example 6 of PCT Patent Application No. PCT / US2014 / 033566, the at least one compound of Formula A was selected to enter clinical trials in patients with advanced cancer. The entire contents of US Patent No. 8,877,803 and PCT Patent Application No. PCT / US2014 / 033566 are incorporated herein by reference.

Protein kinases are a family of enzymes that regulate a variety of cellular processes, including cell growth, cell proliferation, cell differentiation, and metabolic effects. Protein kinases transmit cell growth signals through phosphorylation of pathway partners. Therefore, any kinase that pharmacologically inhibits a given signal transduction cascade can block transmission along the entire pathway. In addition, it is known that protein kinases play a role in disease states and diseases, for example, kinase mutations and / or overexpression of kinases frequently occur in many cancers, resulting in hyperactivation activity, which is often associated with uncontrolled cell growth . Therefore, cancer stem cell pathway kinase (CSCPK) is an important therapeutic target for the treatment of various cancers (see, for example, US Patent No. 8,299,106). Non-limiting examples of CSCPKs include STK33, MELK, AXL, p70S6K, and PDGFR α.

Activation of CSCPK PDGFR α (receptor tyrosine kinase (RTK)) by PDGF ligands can trigger the signal transduction cascade to activate the gene expression required for cell proliferation, angiogenesis and apoptosis. PDGFRα is a class III receptor tyrosine kinase and it is related to the CFS-1 receptor / c-fms and stem cell growth factor / c-kit proto-oncogene family. The PDGFR α pathway (which is active in early fetal development) is also found in many cancers (including hepatocellular carcinoma (HCC), head and neck cancer, brain tumors, gastrointestinal tumors, skin cancer, prostate cancer, ovarian cancer, breast cancer, sarcoma, and leukemia ) To reactivate. In addition, PDGFR α activation has recently been shown to play a key role in bone metastasis of prostate cancer. Use monoclonal antibodies Specific targeting of PDGFRα leads to a significant reduction in tumor cell proliferation and survival with minimal toxicity. The disruption of PDGFR α signaling may be a viable target for treating a wide range of cancers with minimal toxicity.

CSCPK STK33 or human serine / threonine kinase 33 is a member of the Ca ²⁺ / calmodulin-dependent kinase family (CAMK). Although its function in normal biology is not fully understood, STK33 may play a special role in the dynamic behavior of the intermediate filament cytoskeleton by vimentin phosphorylation. STK33 knockdown reduces tumor-related gene expression and inhibits cell migration, invasion, and EMT, showing that STK33 may be a mediator of cancer-related signaling pathways. For example, STK33 is involved in the tumorigenesis and progression of hypopharyngeal squamous cell carcinoma (HSCC) (Huang et al. BMC Cancer. (2015) 15:13).

Maternal embryonic leucine zipper kinase (or MELK) is a serine / threonine-CSCPK, which involves cell cycle regulation, stem cell self-renewal, apoptosis and splicing regulation. MELK has broad substrate specificity. For example, MELK3 acts as an activator of apoptosis by phosphorylating and activating MAP3K5 / ASK1. MELK also regulates the cell cycle through the phosphorylation of CDC25B, which triggers the localization of CDC25B at the central body and mandrel pole during mitosis. MELK also shows a possible role in mammary carcinogenesis by inhibiting the pro-apoptotic function of BCL2L14, phosphorylating and inhibiting BCL2L14.

CSCPK AXL receptor tyrosine kinase (or AXL) is a member of the Tyro3-Axl-Mer (TAM) receptor tyrosine kinase subfamily. The encoded protein has an extracellular domain consisting of two N-terminal immunoglobulin-like (IgL) motifs, followed by two fibronectin type III motifs (FNIII). It transduces signals from the extracellular matrix into the cytoplasm by combining vitamin K-dependent protein growth arrest specificity 6 (Gas6). Downregulation of AXL inhibits brain tumor cell growth and invasion (Vajkoczy et al., Proc. Natl. Acad. Sci. U.SA. 200611; 103 (15): 5799-804). Therefore, AXL is a potential mediator of motility and can control the aggressiveness of breast cancer cells (Zhang et al., Cancer Res. (2008) 15; 68 (6): 1905-15).

p70S6K (or p70 S6 kinase) is serine / threonine CSCPK as part of the PI3K / Akt / mTOR / P70S6K signaling pathway. Activation of p70S6K initiates phosphorylation of S6 ribosomal proteins and induces protein synthesis. p70 S6 kinase (p70S6K) is frequently activated in highly malignant human ovarian cancer, showing a possible role in metastasis.

In some specific examples, the at least one compound selected from compounds having formula B may be, for example, a CSCPK inhibitor (for example, compound BBI503). As discussed in US Patent No. 8,299,106, the compound of formula B inhibits CSC proliferation and / or survival. Examples 1-5 of US Patent No. 8,299,106 further provide an exemplary method of synthesizing at least one compound selected from compounds having Formula B. The entire content of US Patent No. 8,299,106 is incorporated herein by reference.

The present disclosure reports a surprising finding that the combination therapy of at least one compound selected from the compound of formula A and at least one compound selected from the compound of formula C is more effective than each compound in reducing the number of cancer cells (including cancer stem cells) The enhanced effect of the effect has a greater effect. For example, the combination therapy disclosed in the present invention, compared to the enhanced efficacy observed after treatment with the compound of Formula A alone and after treatment with Compound C alone, results in enhanced suppression of the performance of cancer stem cell related factors in vitro and in vivo and Enhance and reduce the number of cancer cells in vitro and in vivo.

In one example, at least one compound selected from compounds of formula A is used The combination of (e.g. BBI608) and at least one compound selected from the compound of formula C (e.g. sorafenib) in the treatment of HCC cell lines resulted in a significant reduction of huge tumor cells (Figure 1) The number of balls formed by CSCs decreases (Figure 2). Figure 3 also shows that the tumor volume in the HepG2 xenograft mouse model decreased as a result of treatment with at least one compound of formula A (eg BBI608) compared to the control treatment.

The present disclosure further reports the surprising finding that the combined treatment of at least one compound selected from the compound of formula B and at least one compound selected from the compound of formula C (sorafenib) reduces cancer cells (including cancer stem cells) In terms of proliferation and / or survival, it has greater efficacy than the enhancement effect of either compound acting alone. For example, the combination therapy disclosed in the present invention has enhanced efficacy compared to the treatment with the compound of formula B alone (eg, BBI503) and the treatment with compound C (eg, sorafenib) alone, resulting in enhanced inhibition in vitro and in vivo The performance and enhancement of cancer stemness-related factors reduce the number of cancer cells in vitro and in vivo.

In another example, the compound of formula B alone and in combination with the compound of formula C (eg, sorafenib) has activity against CSCs from HCC cell lines. The compound of formula B not only inhibits cancer stem cell proliferation and / or survival, but also reduces the ability of CSCs to form characteristic spheres in non-adherent stem cell culture medium. In contrast, the equivalent treatment of the compound of formula C has no significant inhibitory activity on the ability to form CSC spheres or the proliferation and / or survival of cancer cells. In contrast, treatment of cancer cells with a combination of a compound of formula B and a compound of formula C enhanced the reduction of colony formation (Figure 4, Figure 5 and Figure 6). Compounds of formula B, such as BBI503, have also been shown to inhibit the expression of cancer stem cell markers such as CD133 and CD44.

In another example, treatment of tumors in a human liver cancer xenograft mouse model (HepG2) with a compound of formula B (eg, BBI503) significantly inhibited tumor growth compared to a control group. Picture 7 It is shown that the average tumor volume of animals treated with the compound of formula B is 50% smaller than the average tumor volume obtained in the control group.

Without intending to be bound by any particular observation or hypothesis, Xian believes that the components of the combination therapy of the disclosure herein work on different pathways associated with cancer cells (eg, CSC). The combined treatment of the compound of formula A and the compound of formula C or the compound of formula B and the compound of formula C results in inhibition of cancer cell proliferation and / or survival greater than the increased efficacy observed after treatment with the compound alone (sometimes referred to as "enhanced" or "Synergy" effect). The compound of formula A can act by inhibiting the STAT3 signaling pathway. Specifically, the compound of formula A can directly bind to activated STAT3 (eg, phosphorylated STAT3) and inhibit its activity, thereby preventing the transcription of STAT3-dependent target genes, which include the stem-associated transcription factor c-MYC, OCT4, SOX2, and β-chain protein. The compound of formula B can inhibit the activity of various malignant-linked serine-threonine kinases (or cancer stem cell pathway kinases (CSCPKs)).

In certain specific examples, disclosed herein is a method for treating cancer, the method comprising administering to a subject in need a therapeutically effective amount of at least one compound selected from compounds of formula A:

Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing, and therapeutically effective amounts of at least one compound selected from compounds of formula C:

Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing.

In certain specific examples, disclosed herein is a method for treating cancer, the method comprising administering to an individual: a therapeutically effective amount of at least one compound selected from compounds of formula B:

Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing, and therapeutically effective amounts of at least one compound selected from compounds of formula C:

Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing.

In some specific examples, a method for treating cancer is disclosed to include In vivo administration of (a) a therapeutically effective amount of at least one first compound selected from cancer dryness inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, And a solvate of any of the foregoing and (b) a therapeutically effective amount of at least one second compound selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceuticals of any of the foregoing Acceptable salts, and solvates of any of the foregoing.

In some specific examples, the cancer stem inhibitor may be, for example, a STAT3 pathway inhibitor.

In some specific examples, the cancer stem inhibitor may, for example, be selected from 2- (1-hydroxyethyl) -naphtho [2,3- b ] furan-4,9-dione, 2 -Acetyl-7-chloro-naphtho [2,3- b ] furan-4,9-dione, 2-acetoyl-7-fluoro-naphtho [2,3- b ] furan-4, 9-diketone, 2-acetonaphtho [2,3- b ] furan-4,9-dione, 2-ethyl-naphtho [2,3- b ] furan-4,9-dione , A prodrug of any of the foregoing, a derivative of any of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing

In some specific examples, the cancer stem inhibitor may be, for example, a cancer stem cell pathway kinase (CASPK) inhibitor. In certain embodiments, the cancer stemness inhibitor can be selected from, for example, compounds having the formula: A prodrug of any of the foregoing, a derivative of any of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing.

In some specific examples, a kit is disclosed that includes (1) at least one first compound selected from the group consisting of a compound of formula A, a compound of formula B, a prodrug, a derivative, and any of the foregoing A pharmaceutically acceptable salt, and a solvate of any of the foregoing, and (2) at least one second compound selected from the group consisting of compounds of formula C, prodrugs, derivatives, any of the foregoing Acceptable salts, and solvates of any of the foregoing, and instructions for administration and / or use.

In some specific examples, a kit is disclosed that includes (1) at least one first compound selected from the group consisting of compounds of formula A, prodrugs, derivatives, and pharmaceutically acceptable salts of any of the foregoing , And a solvate of any of the foregoing, and (2) at least one second compound selected from the group consisting of compounds of formula C, prodrugs, derivatives, and pharmaceutically acceptable salts of any of the foregoing, and Instructions for giving and / or using.

In some specific examples, a kit is disclosed that includes (1) at least one first compound selected from the group consisting of a compound of formula B, a prodrug, a derivative, and a pharmaceutically acceptable salt of any of the foregoing , And the solvates of any of the foregoing, and (2) at least one second compound selected from the group consisting of compounds of formula C, prodrugs, derivatives, pharmaceutically acceptable salts of any of the foregoing, and Solvate of any of the foregoing, and instructions for administration and / or use.

In some specific examples, a kit is disclosed, which comprises (1) at least one first compound selected from the group consisting of cancer stemness inhibitors, prodrugs of any of the foregoing, derivatives of any of the foregoing, any of the foregoing A pharmaceutically acceptable salt of one of them, and a solvate of any of the foregoing; and (2) at least one second compound selected from the group consisting of kinase inhibitors, prodrugs of any of the foregoing, any of the foregoing Derivatives, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing, and instructions for administration and / or use.

Various aspects and specific examples of the disclosure in this article are presented in the following detailed description or will become readily apparent from the following detailed description. It should be understood that both the foregoing general description and the following detailed description are for illustration and explanation only, and are not intended to limit the scope of patent applications.

The following is the definition of terms used in this specification. Unless otherwise indicated, the initial definition provided for a group or term in this document applies to that group or term alone or as part of another group throughout this specification.

When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the limits above and below the numerical values. Generally speaking, in this article, the term "about" is used to modify a numerical value above or below the stated value with a change of 20%, 10%, 5%, or 1%. In some specific examples, the term "about" is used to modify a numerical value above or below the stated value with a 10% change. In some specific examples, the term "about" is used to modify a numerical value above or below the stated value with a 5% change. In some specific examples, the term "about" is used to modify a numerical value above or below the stated value with a 1% change.

When a range of values is recited herein, it is intended to include each value and sub-range within that range. For example, "1-5mg" is intended to include 1mg, 2mg, 3mg, 4mg, 5mg, 1-2mg, 1-3mg, 1-4mg, 1-5mg, 2-3mg, 2-4mg, 2-5mg, 3-4mg, 3-5mg, and 4-5mg.

In this article, the term "giving" is used in its broadest sense. This term refers to any method of introducing a compound or pharmaceutical composition described herein into an individual and may include, for example, introducing the compound systemically, locally, or in situ into the individual. Therefore, the compounds of the disclosure herein (regardless of whether the pharmaceutical composition contains the compound) produced from the pharmaceutical composition in the individual are covered by this term. When this term is used in conjunction with the terms "systemic" or "systemic", it generally refers to systemic absorption or accumulation in vivo of the compound or composition in the bloodstream, as it spreads throughout the body .

The term "individual" generally refers to an organism to which the compounds or pharmaceutical compositions described herein can be administered. The individual may be a mammalian or mammalian cell, which includes humans or human cells. The term also refers to organisms, which include cells or donors or recipients of such cells. In various specific examples, the term "individual" refers to any animal (eg, mammals), including but not limited to humans, mammals, and non-mammalian animals, such as Non-human primates, mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, fish, nematodes, and insects, which are intended to be the compounds or pharmaceutical compositions described herein Recipient of things. In some cases, the terms "individual" and "patient" are used interchangeably in this article when referring to human individuals.

The terms "effective amount" and "therapeutically effective amount" refer to an amount of a compound or pharmaceutical composition described herein that is sufficient to produce the desired result, including but not limited to disease treatment, as set forth below. In certain embodiments, a "therapeutically effective amount" is effective to detectably kill or inhibit the growth or spread of cancer cells, the size or number of tumors, and / or the grade, stage, progression, and / or severity of cancer Of other measures. In certain embodiments, the "therapeutically effective amount" of the compound or pharmaceutical composition refers to the amount of the compound or pharmaceutical composition administered systemically, locally, or in situ (eg, generated in situ in the individual Amount of compound). The therapeutically effective amount may vary depending on the intended application (in-vitro or in vivo) or the individual to be treated and the disease condition (such as the weight and age of the individual, the severity of the disease condition, the mode of administration and the like), It can be easily determined by those with ordinary knowledge in the technical field. This term also applies to doses that induce a specific response in the target cell (such as reducing cell migration). The specific dosage will vary depending on (for example) the weight of the individual, the particular pharmaceutical composition, the individual and his age and the existing health status or risk regarding the health status, the method of administration of the drug to be adopted, the severity of the disease, Whether it combines the administration of other drugs, the timing of the administration, the tissue to which it is administered, and the physical delivery system that carries it.

With regard to the treatment of an individual's cancer, "therapeutically effective amount" means an amount that can cause, for example, one or more of the following effects: (1) inhibit the growth of cancer or tumor (to a certain extent), including reducing or stopping the individual's cancer Cancer progression; (2) Reduce the number of cancer or tumor cells; (3) Reduce Tumor size; (4) inhibit (e.g. reduce or stop) cancer or tumor cell infiltration into surrounding organs; (5) inhibit (e.g. reduce or stop) metastasis; (6) enhance anti-tumor immune response, which may (but not (Must) cause tumor regression or rejection, or (7) reduce one or more symptoms associated with cancer or tumor (to some extent). The therapeutically effective amount can vary depending on factors such as the stage of the disease, the age, sex, and body weight of the individual and the ability of one or more anti-cancer agents to elicit the desired response in the individual. The "therapeutically effective amount" may be, for example, the amount of a compound for which the therapeutically beneficial effect exceeds any toxic or harmful effects caused by the administration of the compound.

For the purposes of this article, the terms "treatment", "improvement", and "promotion" are used interchangeably in this article. These terms pertain to methods for obtaining beneficial or desired results, including but not limited to therapeutic and / or preventive benefits. With regard to therapeutic benefits, it means eradicating or improving the underlying disease being treated. In addition, therapeutic benefits are achieved with one or more of the physiological symptoms associated with the underlying disease being eradicated or improved and improvements observed in the individual (although the individual may still suffer from the underlying disease). For the benefit of prevention, the pharmaceutical composition can be administered to individuals who are at risk of developing a specific disease, or to individuals who are reported to have one or more of the physiological symptoms of the disease (even if the disease has not yet been developed) diagnosis).

As used herein, the term "combination", "combination", or "combination therapy" means administration of at least two different agents (eg, at least one first compound selected from cancer stemness inhibitors and / or at least one option) A second compound from an immunotherapeutic agent, and (optionally one or more additional agents) to treat a disease, condition, or symptom, such as a cancer condition. Such combination / combination therapy may involve administration of an agent before, during, and / or after administration of the second agent. The first medicament and the second medicament can be administered to the individual simultaneously, separately, or successively in separate pharmaceutical compositions. The first agent and the second agent may be administered to the individual through the same or different administration routes. In some In a specific example, the combination therapy comprises a therapeutically effective amount of at least one first compound selected from cancer dryness and a therapeutically effective amount of at least one second compound selected from immunotherapeutic agents.

For example, the at least one first compound selected from cancer stem inhibitors and the at least one second compound selected from kinase inhibitors may have different mechanisms of action. In certain embodiments, the combination therapy will improve the at least one first compound selected from cancer stem inhibitors and the at least one selected from kinases by acting together to have additive, synergistic, or enhanced efficacy The prophylactic or therapeutic efficacy of the second compound of the inhibitor. In certain embodiments, the combination therapy disclosed herein reduces the side effects associated with the at least one first compound selected from cancer stem inhibitors or the at least one second compound selected from kinase inhibitors. The administration of the at least one first compound selected from cancer stem inhibitors and the at least one second compound selected from kinase inhibitors can be separated in time up to several weeks, but more often within 48 hours, and Most often within 24 hours.

As used herein, the term "prodrug" refers to a parent drug molecule derivative that requires spontaneous or enzymatic biotransformation in an organism to release an active drug. For example, a prodrug is a variant or derivative of a compound of formula A, B, or C that has a group cleavable under certain metabolic conditions, and when cleaved, becomes a compound of formula A, B, or C, respectively. Such are pharmacologically inactive in vivo until they become active under physiological conditions due to, for example, solvolysis or enzymatic degradation. Depending on the number of biotransformation steps required to release the active drug in the organism and the number of functional groups present in the precursor form, the prodrug compounds described herein may be referred to as single, double, triple, etc.

Prodrug forms generally provide the advantages of solubility, histocompatibility, or delayed release in mammalian organisms. Commonly known prodrugs of this technique include, but are not limited to, well-known Acid derivatives, such as esters prepared from the reaction of a parent acid with a suitable alcohol, and amides from the reaction of the parent acid compound with amines or basic groups to form amide base derivatives and the like. Other prodrug derivatives can also be combined with other features disclosed herein to improve bioavailability. Those skilled in the art will understand that certain compounds disclosed herein having free amine, amide, hydroxyl or carboxyl groups can be converted into prodrugs. Prodrugs include compounds with amino acid residues or polypeptide chains of two or more (eg, two, three, or four) amino acid residues, which are covalently bonded to the disclosure by peptide bonds The free amine, hydroxyl or carboxylic acid group of the compound. Amino acid residues include 20 naturally-occurring amino acids usually named by three-letter symbols, as well as, for example, 4-hydroxyproline, hydroxylysine, demosine, isochain, 3-methyl Histidine, norvalin, β-alanine, γ-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine. Prodrugs can also include compounds having a carbonate, carbamate, amide, or alkyl ester moiety covalently bound to any of the above-disclosed substituents disclosed herein.

As used herein, the terms "synergistic", "synergistic", "synergistically", or "enhanced" refer to the interaction or combination of two or more components to produce a separation greater than their equivalent The efficacy of the combined efficacy of the sum of the efficacy (or "additive efficacy"). When the compound is (1) co-formulated and administered or delivered simultaneously in a combination formulation, (2) is delivered alternately or in parallel with separate formulations; or (3) synergistic effects can be obtained by other inoculation methods. When delivered in an alternating treatment, when the compound is administered or delivered sequentially, a synergistic effect can be obtained, for example in separate tablets, pills or capsules, or different injections by separate syringes. Generally, during alternate treatments, for example, continuous administration, that is, continuous administration of an effective dose of each active ingredient, and in combination therapy, effective administration of two or more active ingredients together. The synergistic anticancer efficacy effect means that the anticancer efficacy is greater than the pure additive efficacy predicted by each compound administered alone in combination.

As used herein, the term "cancer stem inhibitor" refers to cancer stemness or performance that can target, reduce, inhibit, interfere with, or regulate at least one of a plurality of cancer stem genes (eg, produce functional products such as A protein) of at least one of a plurality of pathways. The expression or expression protein can be used as the biomarker of the corresponding cancer stem gene. Examples of such biomarkers include but are not limited to β-chain protein, NANOG, SMO, SOX2, STAT3, AXL, ATM, c-MYC, KLF4, SURVIVIN, or BMI-1. Cancer stemness inhibitors may alter cancer stem cell growth as well as heterogeneous cancer cell growth.

In certain embodiments, the cancer stemness inhibitor can be, for example, a small molecule that binds to the protein encoded by the cancer stemness gene. In some specific examples, the cancer stem inhibitors are biological, such as recombinant binding proteins or peptides (eg, APTSTAT3; see Kim et al. Cancer Res. (2014) 74 (8): 2144-51) or nucleic acids (Eg STAT3 aiRNA; see US Patent No. 9,328,345, the contents of which are incorporated herein in its entirety), or its conjugate, which binds to the protein encoded by the cancer stem gene. In some specific examples, the cancer stem inhibitor may be, for example, a cell. In some specific examples, the cancer stem inhibitor may be, for example, a STAT3 inhibitor (eg, one that binds to STAT3 and inhibits its biological activity (see Furtek et al., ACS Chem. Biol., 2016, 11 (2) , pp 308-318)). In some specific examples, the cancer stem inhibitor may be, for example, a CSCPK inhibitor.

In certain embodiments, the cancer dryness inhibitor may be, for example, at least one selected from 2- (1-hydroxyethyl) -naphtho [2,3- b ] furan-4,9-dione 、 2-Acetyl-7-chloro-naphtho [2,3- b ] furan-4,9-dione, 2-acetoyl-7-fluoro-naphtho [2,3- b ] furan- 4,9-diketone, 2-acetonaphtho [2,3- b ] furan-4,9-dione, or 2-ethyl-naphtho [2,3- b ] furan-4,9 -Diketone compounds, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing.

In some specific examples, the cancer stemness inhibitor may be, for example, at least one compound selected from, for example, the following compounds having the following formula: A prodrug of any of the foregoing, a derivative of any of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing.

In certain embodiments, the cancer stem inhibitors disclosed herein can be administered in amounts ranging from about 300 mg to about 700 mg. In certain embodiments, the cancer stemness inhibitor can be administered in an amount ranging from about 700 mg to about 1200 mg. In certain embodiments, the cancer stemness inhibitor can be administered in an amount ranging from about 800 mg to about 1100 mg. In certain embodiments, the cancer stemness inhibitor can be administered in an amount ranging from about 850 mg to about 1050 mg. In certain embodiments, the cancer stemness inhibitor can be administered in an amount ranging from about 960 mg to about 1000 mg.

In some specific examples, the total amount of the cancer stem inhibitor can be administered once a day. In some specific examples, the cancer dryness inhibitor may be administered daily at a dose of about 480 mg. In some specific examples, the cancer stemness inhibitor may be administered daily at a dose of about 960 mg. In certain embodiments, the cancer stemness inhibitor can be administered daily at a dose of about 1000 mg. In some specific examples, the total amount of the cancer stem inhibitor may be administered as separate agents more than once a day, such as twice daily (BID) or more. In some specific examples, the cancer stem inhibitor may be administered at a dose of about 240 mg twice daily. In some specific examples, the cancer dryness inhibitor can be administered at a dose of about 480 mg twice daily. In some specific examples, the cancer stem inhibitor may be administered at a dose of about 500 mg twice daily. In some specific examples, the cancer stem inhibitor can be administered orally.

In certain specific examples, the cancer stemness inhibitor may be, for example, at least one compound selected from compounds having Formula A. As used herein, the interchangeable terms "compounds of formula A", "these compounds of formula A" and "compound A" each mean a compound selected from compounds of formula A:

Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing.

In certain embodiments, the prodrugs and derivatives of the compound of formula A can be, for example, STAT3 inhibitors. Non-limiting examples of prodrugs of compounds having Formula A include, for example, the phosphate esters and phosphodiester described as compound numbers 4011 and 4012 in U.S. Pre-Grant Publication No. 2012/0252763 and in U.S. Patent No. 9,150,530 Describe suitable compounds. Non-limiting examples of derivatives of compounds having Formula A include, for example, the derivatives disclosed in US Patent No. 8,977,803. The disclosures of U.S. Pre-Grant Publication No. 2012/0252763 and U.S. Patent Nos. 9,150,530 and 8,977,803 are incorporated herein by reference in their entirety.

Compounds of formula A as shown below

It is also known as 2-acetonaphtho [2,3-b] furan-4,9-dione, napabucasin, BBI608 or BB608, and includes tautomers thereof.

A suitable method for the preparation of 2-acetonaphtho [2,3-b] furan-4,9-dione (including its crystalline form) and other cancer drying inhibitors is described in WO 2009/036099, WO 2009 / 036101, It is described in WO 2011/116398, WO 2011/116399, and the PCT application jointly disclosed by WO 2014/169078. The contents of each of these applications are incorporated by reference in their entirety.

In certain embodiments, Compound A can be administered in an amount ranging from about 80 mg to about 1500 mg. In certain embodiments, Compound A can be administered in an amount ranging from about 160 mg to about 1000 mg. In certain embodiments, Compound A can be administered in an amount ranging from about 300 mg to about 700 mg a day. In certain embodiments, Compound A can be administered in an amount ranging from about 700 mg to about 1200 mg. In certain embodiments, Compound A can be administered in an amount ranging from about 800 mg to about 1100 mg. In certain embodiments, Compound A can be administered in an amount ranging from about 850 mg to about 1050 mg. In some specific examples, Compound A can be administered in an amount ranging from about 960 mg to about 1000 mg. In some specific examples, the total amount of Compound A can be administered, for example, once a day. In some specific examples, Compound A is administered daily at a dose of about 480 mg. In some specific examples, Compound A can be administered, for example, at a dose of about 960 mg daily. In certain embodiments, Compound A can be administered, for example, at a dose of about 1000 mg daily. In certain embodiments, the total amount of Compound A can be administered, for example, in divided doses more than once a day, such as twice daily (BID) or more. In certain embodiments, Compound A can be administered in an amount ranging from about 80 mg twice daily to about 750 mg twice daily. In certain embodiments, Compound A can be administered in an amount ranging from about 80 mg twice daily to about 500 mg twice daily. In some specific examples, Compound A can be administered, for example, at a dose of about 240 mg twice daily. In some specific examples, Compound A can be administered, for example, at a dose of about 480 mg twice daily. In certain embodiments, Compound A can be administered, for example, at a dose of about 500 mg twice daily. In some specific examples, Compound A may, for example Service vote.

In certain embodiments, the cancer stemness inhibitor can be, for example, at least one compound selected from compounds having formula B. As used herein, the interchangeable terms "compounds of formula B", "these compounds of formula B", and "compound B" each mean a compound selected from compounds of formula B:

Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing.

In some specific examples, the cancer stemness inhibitor may be, for example, a cancer stem cell pathway kinase (CSCPK) inhibitor, STK33 inhibitor, MELK inhibitor, AXL inhibitor, p70S6K inhibitor, PDGFR α inhibitor, Or NANOG inhibitor. In some specific examples, the cancer stem inhibitor may be, for example, a cancer stem cell pathway kinase (CSCPK) inhibitor. In some specific examples, the cancer stem inhibitor may be, for example, an STK33 inhibitor. In certain specific examples, the cancer stem inhibitor may be, for example, a MELK inhibitor. In some specific examples, the cancer stem inhibitor may be, for example, an AXL inhibitor. In some specific examples, the cancer stem inhibitor may be, for example, a p70S6K inhibitor. In some specific examples, the cancer stem inhibitor may be, for example, a PDGFR α inhibitor. In some In a specific example, the cancer stem inhibitor may be, for example, a NANOG inhibitor.

In some specific examples, the compound of formula B, and derivatives thereof may be, for example, cancer stem cell pathway kinase (CSCPK) inhibitors. In some specific examples, the compound of formula B, and derivatives thereof may include, for example, STK33, MELK, AXL, p70S6K, and PDGFR α inhibitors. In some specific examples, the at least one compound is selected from compounds having formula B, and derivatives thereof may be, for example, STK33 inhibitors. In some specific examples, the at least one compound is selected from compounds having Formula B, and derivatives thereof may be, for example, MELK inhibitors. In some specific examples, the at least one compound is selected from compounds having formula B, and derivatives thereof may be, for example, AXL inhibitors. In certain embodiments, the at least one compound is selected from compounds having formula B, and derivatives thereof can be, for example, p70S6K inhibitors. In some specific examples, the at least one compound is selected from compounds having formula B, and derivatives thereof may be, for example, PDGFR α inhibitors. In some specific examples, the at least one compound is selected from compounds having formula B, and derivatives thereof, which can inhibit NANOG performance. Non-limiting examples of compounds having Formula B, and derivatives thereof may include, for example, derivatives disclosed in U.S. Patent No. 8,299,106 and PCT Patent Application Publication No. WO2014160401. The entire contents of U.S. Patent No. 8,299,106 and PCT Patent Application Publication No.WO2014160401 are incorporated herein by reference.

In some specific examples, the CSCPK inhibitor may be selected from, for example, compounds having the formula: Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing.

In some specific examples, the CSCPK inhibitor may be, for example, to At least one compound selected from compounds having formula B.

Suitable methods for preparing compounds of formula B and their derivatives are described in US Patent No. 8,299,106 and PCT Patent Application Publication WO2014160401; the entire contents of each of its applications are incorporated herein by reference.

In some specific examples, the CSCPK inhibitor may be administered in an amount ranging from about 20 mg to about 600 mg. In some specific examples, the CSCPK inhibitor may be administered in an amount ranging from about 50 mg to about 500 mg. In some specific examples, the CSCPK inhibitor may be administered in an amount ranging from about 80 mg to about 400 mg. In some specific examples, the CSCPK inhibitor may be administered in an amount ranging from about 80 mg to about 300 mg. In some specific examples, the CSCPK inhibitor can, for example, be administered once a day. In certain embodiments, CSCPK inhibitors can be administered, for example, at a daily dose of about 100 mg. In certain embodiments, CSCPK inhibitors can be administered, for example, at a daily dose of about 200 mg. In certain embodiments, CSCPK inhibitors can be administered, for example, at a daily dose of about 300 mg. In certain embodiments, the total amount of CSCPK inhibitor can be, for example, a single daily dose. In some specific examples, the total amount of CSCPK inhibitor may, for example, be administered in divided doses more than once a day, such as twice daily (BID) or more. In some specific examples, the CSCPK inhibitor can, for example, be administered once daily at a dose of about 100 mg. In some specific examples, the CSCPK inhibitor can, for example, be administered once daily at a dose of about 200 mg. In some specific examples, the CSCPK inhibitor can, for example, be administered orally.

In certain embodiments, Compound B can be administered in an amount ranging from about 20 mg to about 600 mg. In certain embodiments, Compound B can be administered in an amount ranging from about 50 mg to about 500 mg. In certain embodiments, Compound B can range from about 80 mg to about 400 mg Amount given. In certain embodiments, Compound B can be administered in an amount ranging from about 80 mg to about 300 mg. In some specific examples, Compound B may, for example, be administered once daily. In certain embodiments, Compound B can be administered, for example, at a daily dose of about 100 mg. In certain embodiments, Compound B can be administered, for example, at a daily dose of about 200 mg. In some specific examples, Compound B can be administered, for example, at a dose of about 300 mg per day. In certain embodiments, the total amount of Compound B can be administered, for example, in a single daily dose. In certain embodiments, the total amount of Compound B can be administered, for example, in divided doses more than once a day, such as twice daily (BID) or more. In certain embodiments, Compound B can be administered, for example, at a daily dose of about 100 mg. In certain embodiments, Compound B can be administered, for example, at a daily dose of about 200 mg. In some specific examples, Compound B can, for example, be administered orally.

As used herein, the term "kinase inhibitor" or "kinase inhibitors" refers to molecules that can target, reduce, inhibit, interfere with, or modulate at least one activity of a plurality of protein kinases. Examples of such protein kinases include, but are not limited to, intracellular kinases (eg, c-CRAF, BRAF, and mutant BRAF) and cell surface kinases (eg, KIT, FLT-3, RET, RET / PTC, VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR-ß). Examples of kinase inhibitors include, but are not limited to, afatinib (EGFR / ErbB2 inhibitors), axitinib (axitinib), (VEGFR1 / VEGFR2 / VEGFR3 / PDGFRB / c-KIT inhibitors), Bosutinib (Bcr-Abl / SRC inhibitor), cetuximab (EGFR inhibitor), cobimetinib (MEK inhibitor), crizotinib (crizotinib) ALK / Met inhibitor), cabozantinib (RET / MET / VEGFR2 inhibitor), dasatinib (multiple kinase inhibitor), entrectinib (TrkA / TrkB / TrkC / ROS1 / ALK inhibitor), erlotinib (EGFR inhibitor), fostamatinib (Syk inhibitor), gefitinib (EGFR inhibition) Agent), ibrutinib (BTK inhibitor), imatinib (Bcr-Abl inhibitor), lapatinib (EGFR / ErbB2 inhibitor), levatinib ( lenvatinib) (VEGFR2 inhibitor), muritinib (mubritinib), nilotinib (Bcr-Abl inhibitor), pazopanib (VEGFR2 / PDGFR / c-kit inhibitor), Pegaptanib (VEGF inhibitor), ruxolitinib (JAK inhibitor), sorafenib (multiple kinase inhibitor), sunitinib (multikinase inhibitor) , SU6656 (Src inhibitor), vandetanib (RET / VEGFR / EGFR inhibitor), or vemurafenib (BRAF inhibitor).

In certain embodiments, the kinase inhibitor may be, for example, at least one compound selected from compounds having formula C. As used herein, the terms "compound of formula C" and "compound C" are used interchangeably, and each means a compound selected from compounds of formula C:

Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. Compound C is also known as 4- [4-[[4-chloro-3- (trifluoromethyl) phenyl] aminomethylaminoamino] phenoxy] -N-methyl-pyridine-2-carboxamide Amine, Nexavar, or sorafenib.

In certain embodiments, Compound C can be administered in an amount ranging from about 80 mg to about 1500 mg. In certain embodiments, Compound C can range from about 100 mg to about 1200 mg Encircle the amount. In certain embodiments, Compound C can be administered in an amount ranging from about 200 mg to about 1000 mg a day. In certain embodiments, Compound C can be administered in an amount ranging from about 400 mg to about 900 mg. In certain embodiments, Compound C can be administered in an amount ranging from about 600 mg to about 900 mg. In certain embodiments, Compound C can be administered in an amount ranging from about 700 mg to about 900 mg. In some specific examples, Compound C can be administered in an amount of about 800 mg. In some specific examples, the total amount of compound C can be administered, for example, once a day. In certain embodiments, the total amount of compound C can be administered, for example, in divided doses more than once a day, such as twice daily (BID) or more. In certain embodiments, Compound C can be administered in an amount ranging from about 80 mg twice daily to about 750 mg twice daily. In certain embodiments, Compound C can be administered in an amount ranging from about 80 mg twice daily to about 600 mg twice daily. In some specific examples, Compound C may, for example, be administered at a dose of about 200 mg twice daily. In some specific examples, Compound C may, for example, be administered at a dose of about 400 mg twice daily. In certain embodiments, Compound C can be administered orally, for example. In some specific examples, Compound C can be administered, for example, on an empty stomach. In certain embodiments, Compound C can be administered, for example, about 1 hour before a meal or about 2 hours after a meal.

For the purposes of this article, the terms "progress", "progressive" and "progress" refer to at least one of the following: (1) Response to previous treatment (such as chemotherapy) of progressive disease (PD); ( 2) One or more new lesions appear after treatment with previous treatments (eg, chemotherapy); at least 5% (eg, 10%, 20%) of the total diameter of the target lesion increases as (3), as The reference value of the minimum sum on the study (if the baseline sum is the minimum value on the study, this includes the baseline sum).

As used herein, the term "sensitized" means to make previous treatments (such as chemical (Treatment) Infusion method is for individuals who are resistant, non-reactive, or slightly reactive to become sensitive, reactive, or more reactive to the treatment (eg, chemotherapy) infusion method.

The term "cancer" in individuals refers to cells with typical characteristics of cells that cause cancer (such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain morphological characteristics) appear. Generally, cancer cells may be in the form of tumors or clumps, but such cells may exist alone in an individual, or may circulate in the bloodstream as independent cells (such as leukemia or lymphoma cells). As used herein, examples of cancer include, but are not limited to, lung cancer, pancreatic cancer, bone cancer, skin cancer, head or neck cancer, cutaneous melanoma or intraocular melanoma, breast cancer, uterine cancer, ovarian cancer, peritoneal cancer, Colon cancer, rectal cancer, colorectal adenocarcinoma, anal cancer, stomach cancer, gastric cancer, gastrointestinal cancer, gastric adenocarcinoma, adrenal cortical cancer, uterine cancer, tubal epithelial cancer, endometrial cancer Epithelial cancer, vaginal epithelial cancer, vulvar epithelial cancer, Hodgkin's disease, esophageal cancer, gastroesophageal junction cancer, gastroesophageal adenocarcinoma, chondrosarcoma, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid, vice Cancer of the thyroid, cancer of the adrenal gland, sarcoma of soft tissue, Ewing's sarcoma, cancer of the urethra, cancer of the penis, prostate cancer, bladder cancer, testicular cancer, cancer of the ureter, epithelial carcinoma of the pelvis, mesothelioma, hepatocellular carcinoma Gallbladder cancer, kidney disease, renal cell epithelial cancer, chronic or acute leukemia, lymphocytic lymphoma, neoplasms of the central nervous system (CNS), spinal tumors, brainstem gliomas, pleomorphic neurons Glioblastoma, astrocytoma, schwannomas, ependymoma, medulloblastoma, meningiomas, squamous cell carcinoma, pituitary adenoma, including refractory variants of any of the above cancers , Or a combination of one or more of the above cancers. Some lines of exemplary cancer are included in the general term and are included in this term. For example, urinary cancer (a general term) may include bladder cancer, prostate cancer, kidney disease, testicular cancer, and the like; and hepatobiliary cancer (another general term) includes liver cancer (which itself is a general term that includes Hepatocellular carcinoma or cholangiocarcinoma), gallbladder cancer, gallbladder cancer, or pancreatic cancer. Both urinary cancer and hepatobiliary cancer are covered by the disclosure of this article and are included in the term "cancer".

As used herein, "cancer" may include the term "solid tumor". As used herein, the term "solid tumor" refers to such conditions (such as cancer) that form abnormal tumor masses (such as sarcoma, epithelial cancer, and lymphoma). Examples of solid tumors include, but are not limited to, non-small cell lung cancer (NSCLC), neuroendocrine tumors, thymoma, fibroids, metastatic colorectal cancer (mCRC), and the like. In some specific examples, the solid tumor disease may be, for example, adenocarcinoma, squamous cell carcinoma, large cell epithelial carcinoma, and the like.

In some specific examples, the cancer may be, for example, esophageal cancer, gastroesophageal junction cancer, gastroesophageal adenocarcinoma, gastric cancer, chondrosarcoma, colorectal adenocarcinoma, breast cancer, ovarian cancer, head and neck cancer, melanoma, gastric adenocarcinoma, Lung cancer, pancreatic cancer, renal cell epithelial cancer, hepatocellular carcinoma, cervical cancer, brain tumor, multiple myeloma, leukemia, lymphoma, prostate cancer, cholangiocarcinoma, endometrial cancer, small intestine adenocarcinoma, uterine sarcoma, Or adrenocortical carcinoma. In certain embodiments, the cancer may be, for example, esophageal cancer, gastroesophageal junction cancer, gastroesophageal adenocarcinoma, colorectal adenocarcinoma, breast cancer, ovarian cancer, head and neck cancer, melanoma, gastric adenocarcinoma, lung cancer, pancreatic cancer , Renal cell epithelial cancer, hepatocellular carcinoma, cervical cancer, brain tumors, multiple myeloma, leukemia, lymphoma, prostate cancer, cholangiocarcinoma, endometrial cancer, small intestinal adenocarcinoma, uterine sarcoma, or adrenocortical carcinoma. In some specific examples, the cancer may be breast cancer, for example. In some specific examples, the cancer may be, for example, colorectal adenocarcinoma. In some specific examples, the cancer may be, for example, adenocarcinoma of the small intestine. In some specific examples, the cancer may be, for example, hepatocellular carcinoma. In some specific examples, the cancer may be, for example, head and neck cancer. In some specific examples, the cancer may be, for example, renal cell epithelial cancer. In some specific examples, the cancer may be, for example, ovarian cancer. In some specific examples, the cancer may For example, prostate cancer. In some specific examples, the cancer may be, for example, lung cancer. In some specific examples, the cancer may be, for example, uterine sarcoma. In some specific examples, the cancer may be, for example, esophageal cancer. In some specific examples, the cancer may be, for example, endometrial cancer. In some specific examples, the cancer may be, for example, cholangiocarcinoma. In some specific examples, each of the cancers can be, for example, unresectable, advanced, refractory, relapsed, or metastatic.

As used herein, the term "salt" includes acid salts and / or alkali salts formed with inorganic and / or organic acids and bases. For the purposes of this article, the term "pharmaceutically acceptable salts" refers to these (within reasonable medical judgment) applicable to contact with an individual's tissues without excessive toxicity, irritation, allergic reactions and / or Salts that are similar and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are widely known in the technical field. For example, Berge et al. Describe in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences (1977) 66: 1-19.

Pharmaceutically acceptable salts can be formed with inorganic or organic acids. Non-limiting examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Non-limiting examples of suitable organic acids include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. Other non-limiting examples of suitable pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzenesulfonate, benzoate, sulfuric acid Hydrogen salt, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanopropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, Fumarate, glucose enanthate, glycerol phosphate, gluconate, hemisulfate, enanthate, caproate, iodate, 2-hydroxy-ethanesulfonate, lactobionate, lactic acid Salt, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate , Oxalate, palmitate, pamoate, jelly acid Salt, persulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate , P-toluenesulfonate, undecanoate, and valerate. In certain embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, Succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, amygdalic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the compound with a suitable base or acid (respectively). Non-limiting examples of pharmaceutically acceptable salts derived from bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N ⁺ (C _1-4 alkyl) ₄ salts. Non-limiting examples of suitable alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Further non-limiting examples of suitable pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cations formed using counter ions such as halide, hydroxide, carboxylate, sulfuric acid Salt, phosphate, nitrate, low-carbon alkyl sulfonate, and aryl sulfonate. Non-limiting examples of suitable organic bases from which salts can be derived include primary amines, secondary amines, tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange Resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some specific examples, the pharmaceutically acceptable base addition salts may be selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

The term "solvate" represents an aggregate that contains one or more molecules of a compound of the disclosure herein and a solvent of one or more molecules. Solvates of compounds disclosed herein include, for example, hydrates.

The at least one compound disclosed herein may be in the form of a pharmaceutical composition. In In some specific examples, the pharmaceutical composition may include at least one compound having Formula A and at least one pharmaceutically acceptable carrier. In some specific examples, the pharmaceutical composition may comprise at least one compound of formula B and at least one pharmaceutically acceptable carrier. In some specific examples, the pharmaceutical composition may comprise at least one compound of formula C and at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition can include one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds can be converted into at least one compound of Formula A in one body (ie, Prodrug). In certain embodiments, the pharmaceutical composition can include one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds can be converted into at least one compound of formula B in one body (ie, Prodrug). In some specific examples, the pharmaceutical composition may include one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds can be converted into at least one compound of formula C (ie, Prodrug).

As used herein, the term "carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as, for example, a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which ( For example) involves or is capable of carrying or transporting a compound from one organ (or body part) to another organ (or body part) for an individual. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Non-limiting examples of pharmaceutically acceptable carriers, carriers, and / or diluents include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxyl groups Sodium methylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower Oil, sesame oil, olive oil, corn oil and soybean oil; glycol, such as propylene glycol; polyol, such as glycerin Oil, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; etc. Salt water; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate) and polyethylene oxide-polypropylene oxide copolymers as well as coloring agents, release agents, coating agents, sweeteners, flavoring agents With flavoring agents, preservatives and antioxidants can also appear in the pharmaceutical composition.

The pharmaceutical composition disclosed herein suitable for oral administration can be in the form of capsules, sachets, pills, lozenges, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth) Powders, granules, solutions in aqueous or non-aqueous liquids, suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions, water-in-oil emulsions, elixirs, syrups, lozenges (using inert substrates such as gelatin, Glycerin, sucrose, and / or gum arabic) and / or mouthwash, etc., each containing a predetermined amount of the at least one compound disclosed herein.

The pharmaceutical composition disclosed herein can be administered in the form of a bolus, lick, or paste.

Solid dosage forms for oral administration (capsules, lozenges, pills, dragees, powders, granules and the like) can be combined with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and / or Or a mixture of any of the following: fillers or boosters, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binding agents, such as (for example) carboxymethyl cellulose, alginate , Gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; humectants such as glycerin; disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicate Sodium carbonate, and sodium starch glycolate; solution blockers, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glyceryl monostearate, and Polyethylene oxide-polypropylene oxide copolymer; absorbents such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof ; With colorants. In the case of capsules, lozenges and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions can also be used as soft or hard filled gelatin capsules using excipients such as lactose (1actose) or lactose (milk sugar), and high molecular weight polyethylene glycol and the like Filling agent.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid dosage form may contain inert diluents commonly used in the art, such as, for example, water or other solvents, co-solvents and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate Ester, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofuranol, Polyethylene glycol, fatty acid esters of sorbitan, and mixtures thereof. In addition, cyclodextrin (eg, hydroxypropyl-β-cyclodextrin) can be used to dissolve the compound.

The pharmaceutical composition may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, coloring agents, flavoring agents, and preservatives. In addition to the compounds according to the disclosure of the present case, the suspension may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, partial hydrogen peroxide Aluminum, bentonite, agar-agar, tragacanth, and mixtures thereof.

The pharmaceutical compositions disclosed herein for rectal or vaginal administration can be in the form of suppositories, which can be prepared by mixing one or more compounds according to the disclosure with one or more suitable non-irritating excipients or carriers Preparation, the non-irritating excipient or carrier contains (for example) Cocoa butter, polyethylene glycol, suppository wax, or salicylate, which is solid at room temperature but liquid at body temperature, and therefore will melt in the rectum or vaginal cavity and release the compounds disclosed herein. Pharmaceutical compositions suitable for vaginal administration may also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be appropriate in the art.

Dosage forms for topical or transdermal administration of the pharmaceutical composition or pharmaceutical lozenge disclosed herein may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalations Agent. The pharmaceutical composition or pharmaceutical lozenge can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

In addition to the pharmaceutical compositions or lozenges disclosed herein, the ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, Cellulose derivatives, polyethylene glycol, polysiloxane, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

In addition to the pharmaceutical composition or medicinal lozenges disclosed herein, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or such substances Of mixture. In addition, the spray may contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Eye formulations (eye ointments, powders, solutions and the like) are also covered within the scope of the disclosure herein.

Pharmaceutical compositions suitable for parenteral administration may contain at least another pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, emulsion, or sterile powder, which can be restored immediately before use Into a sterile injectable solution or dispersion, which may contain antioxidants Agents, buffers, bacteriostatic agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

In some specific examples, the compositions described herein may include at least one compound selected from compounds of Formula A and pharmaceutically acceptable salts and solvates thereof and one or more surfactants. In some specific examples, the surfactant may be, for example, sodium lauryl sulfate (SLS), sodium lauryl sulfate (SDS), or one or more polyoxyglycerides. For example, the polyoxyglyceride may be lauryl polyoxyglyceride (sometimes referred to as Gelucire ^™ ) or linoleyl polyoxyglyceride (sometimes referred to as Labrafil ^™ ). Examples of such compositions are shown in PCT Patent Application No. PCT / US2014 / 033566, the contents of which are incorporated herein in their entirety.

The present invention provides the following further specific examples: suitable pharmaceutical formulations with selected particle size distributions and the most ideal particle size distribution for identification, suitable drug ingestion methods, doses and intervals, and preparation of 2-ethynyl naphtho , 3-b] furan-4,9-dione (including its crystalline form) suitable methods, and further specific suitable methods for cancer dryness and inhibitor kinase inhibition, such as WO2009 / 036099, WO 2009/036101 , WO 2011/116398, WO 2011/116399, WO 2014/169078 and WO 2009/033033 are described in the jointly owned PCT application, the entire contents of which are incorporated herein by reference.

In some specific examples, the compositions described herein may include at least one compound selected from compounds of Formula B and pharmaceutically acceptable salts and solvates thereof and one or more surfactants. In some specific examples, the surfactant may be, for example, sodium lauryl sulfate (SLS), sodium lauryl sulfate (SDS), or one or more polyoxyglycerides. For example, the polyoxyglyceride may be lauryl polyoxyglyceride (sometimes referred to as Gelucire ^™ ) or linoleyl polyoxyglyceride (sometimes referred to as Labrafil ^™ ).

In some specific examples, the compounds or pharmaceutical compositions described herein can be administered in combination with any of a variety of known therapies including, for example, chemotherapeutics and other antitumor agents, anti-tumor agents Inflammatory compounds, and / or immunosuppressive compounds. In some specific examples, the compounds, products, and / or pharmaceutical compositions described herein are useful in combination with any of a variety of known therapies, including (by way of non-limiting examples) Surgical treatment and methods, radiation therapy, chemotherapy, and / or hormone or other endocrine-related treatment.

In certain specific examples, disclosed herein is a method of treating cancer in an individual in need of treatment for cancer, the method comprising administering (a) a therapeutically effective amount of at least one first compound selected from cancer stem inhibitors, Prodrug, derivative of the foregoing, pharmaceutically acceptable salt of any of the foregoing, solvate with any of the foregoing, and (b) a therapeutically effective amount of at least one second compound selected from kinase inhibition Agents, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. In certain specific examples, the at least one selected from the group consisting of cancer stemness inhibitors, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The compound may be included in the pharmaceutical composition. In certain embodiments, the at least one is selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The second compound may be included in the pharmaceutical composition.

In certain specific examples, the provided herein is a method of treating cancer cells in an individual in need of treatment of cancer, the method comprising administering (a) a therapeutically effective amount of at least one selected from cancer stem inhibitors, the aforementioned A prodrug, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, a first compound with a solvate of any of the foregoing, and (b) a therapeutically effective amount of at least one second compound, which is Selected from kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing Substances, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. In some specific examples, the cancer cell line is in an individual. In certain specific examples, the at least one selected from the group consisting of cancer stemness inhibitors, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The compound may be included in the pharmaceutical composition. In certain embodiments, the at least one is selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The second compound may be included in the pharmaceutical composition.

In some specific examples, disclosed herein is a method of inhibiting, reducing, and / or reducing cancer stem cell survival and / or self-renewal, which method is administered (a) a therapeutically effective amount of at least one first compound selected from Cancer dryness inhibitor, prodrug of the foregoing, derivative of the foregoing, pharmaceutically acceptable salt of any of the foregoing, solvate with any of the foregoing, and (b) a therapeutically effective amount of at least one first The two compounds are selected from kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. In some specific examples, the cancer cell line is in an individual. In some specific examples, the cancer stem cell line is in an individual. In certain specific examples, the at least one selected from the group consisting of cancer stemness inhibitors, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The compound may be included in the pharmaceutical composition. In certain embodiments, the at least one is selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The second compound may be included in the pharmaceutical composition.

In some specific examples, a method for treating cancer that is difficult to treat with traditional chemotherapy and / or target therapy in an individual is disclosed herein, the method administering (a) a therapeutically effective amount of at least one A first compound selected from cancer dryness inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, solvates with any of the foregoing and ( b) a therapeutically effective amount of at least one second compound selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and any of the foregoing Solvate. In some specific examples, the cancer stem cell line is in an individual. In certain specific examples, the at least one selected from the group consisting of cancer stemness inhibitors, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The compound may be included in the pharmaceutical composition. In certain embodiments, the at least one is selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The second compound may be included in the pharmaceutical composition. In some specific examples, the traditional chemotherapy and / or targeted therapy may include administration of at least one compound selected from kinase inhibitors, prodrugs thereof, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing , With any of the aforementioned solvates. In some specific examples, the traditional chemotherapy and / or targeted therapy may include administration of sorafenib.

In some specific examples, disclosed herein is a method of treating relapsed cancer in an individual who has failed surgery, tumor therapy (eg, chemotherapy), and / or radiation therapy, the method administering (a) a therapeutically effective amount of at least one first compound , Which is selected from cancer dryness inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, solvates with any of the foregoing, and (b) therapeutically effective An amount of at least one second compound selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. In some specific examples, the cancer stem cell line is in an individual. In some specific examples, the at least one is selected from cancer stem inhibitors, prodrugs thereof, derivatives thereof, prodrugs The first compound of any one of the pharmaceutically acceptable salts and the solvate of any one of the foregoing may be included in the pharmaceutical composition. In certain embodiments, the at least one is selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The second compound may be included in the pharmaceutical composition.

In some specific examples, disclosed herein is a method of treating or preventing cancer metastasis in an individual, the method administering (a) a therapeutically effective amount of at least one first compound selected from cancer stem inhibitors, the former of the foregoing A medicine, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, a solvate with any of the foregoing, and (b) a therapeutically effective amount of at least one second compound selected from kinase inhibitors , A prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing In some specific examples, the cancer stem cell line is in an individual. In certain specific examples, the at least one selected from the group consisting of cancer stemness inhibitors, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The compound may be included in the pharmaceutical composition. In certain embodiments, the at least one is selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The second compound may be included in the pharmaceutical composition.

In some specific examples, a method for preventing relapse or inhibiting cancer regrowth or recurrence is disclosed herein. The method administers (a) a therapeutically effective amount of at least one first compound, which is selected from cancer stem inhibitors, Prodrugs of the above, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, solvates with any of the foregoing, and (b) a therapeutically effective amount of at least one second compound selected from Kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. In some specific In one example, the cancer stem cell line is in an individual. In certain specific examples, the at least one selected from the group consisting of cancer stemness inhibitors, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The compound may be included in the pharmaceutical composition. In certain embodiments, the at least one is selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The second compound may be included in the pharmaceutical composition. In some specific examples, the method is part of adjuvant therapy. In certain embodiments, the method comprises administering the combination therapy of the present invention after or at the same time as the initial treatment of cancer. In some specific examples, the primary treatment is selected from chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.

In some specific examples, disclosed herein is a method of sensitizing or resensitizing cells to at least one kinase inhibitor, the method comprising administering a therapeutically effective amount of at least one first compound selected from cancer stem suppression Agents, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. In some specific examples, the at least one kinase inhibitor is sorafenib. In certain embodiments, the method comprises administering a therapeutically effective amount of at least one second compound selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable of any of the foregoing Accepted salts, solvates with any of the foregoing. In certain specific examples, the at least one selected from the group consisting of cancer stemness inhibitors, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The compound may be included in the pharmaceutical composition. In certain embodiments, the at least one is selected from the group consisting of kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing The second compound may be included in the pharmaceutical composition.

In some specific examples, the cancer may be, for example, hepatocellular carcinoma. In some specific examples, the cancer may be, for example, cholangiocarcinoma.

In some specific examples, the cancer may be unresectable. In some specific examples, the cancer may be advanced. In some specific examples, the cancer may be refractory. In some specific examples, the cancer may be relapsed. In some specific examples, the cancer may be metastatic. In some specific examples, the cancer may be associated with STAT3 overexpression. In some specific examples, the cancer may be associated with nuclear β-chain protein localization.

Examples

The following examples are provided to further illustrate the different features of the present invention. These examples also illustrate useful methodology for implementing the invention. These embodiments do not limit the claimed invention.

The method disclosed herein comprises administering to a subject in need a combination of a therapeutically effective amount of at least one compound selected from cancer stem inhibitors and a therapeutically effective amount of at least one compound selected from kinase inhibitors.

Example 1: Combination treatment with Compound A (BBI608) and Compound C (Sorafenib) enhances inhibition of bulk cancer cell colony formation in vitro

A colony formation assay was used to examine the ability of a large number of cancer cells to undergo clonogenic expansion after combined treatment with Compound A and Compound C. For these studies, human HCC cell lines (HepG2, 1000 cells / well) were seeded in 6-well dishes. 24 hours after inoculation, cells were treated with DMSO (control group), Compound A alone (0.15 μM), Compound C alone (2 μM) or a combination of Compound A (0.15 μM) and Compound C (2 μM). The cells are then cultured for 7-10 days until the visible colonies are formed.

As shown in Figure 1, use a combination of Compound A and Compound C ("combo") Treatment, compared to treatment with Compound A alone (BBI608) or Compound C alone (Sorafenib) resulted in enhanced inhibition of HCC colony formation.

Example 2: Combination treatment with Compound A (BBI608) and Compound C (Sorafenib) enhances inhibition of cancer stem cell spheroids formation in vitro

After using a combination of Compound A (BBI608) and Compound C (Sorafenib) ("combo") to treat cancer cells, cancer stem cell spheroid formation (ie, spherogenesis) was examined. Sk-Hep1, Huh7 and HepG2 cells alone were grown in suspension for 48 hours, then compound A (BBI608; 1.6 μM) and compound C (Sorafenib; 2 μM) alone at concentrations of 1.6 μM and 2 μM, respectively. Or a combination of Compound A (BBI608) and Compound C (Sorafenib) was incubated for 24 hours. The cells were then washed and incubated in standard cell culture medium for another 24 hours. The cells were then examined and photographed using an interference phase contrast (DIC) microscope. As Tryphan Blue stains the cells blue, it indicates the presence of dead cells.

As shown in Figure 2, treatment with a combination of Compound A (BBI608) and Compound C (Sorafenib) ("combo") was compared to Compound A (BBI608) alone or Compound C (Sorafenib) alone Treatment resulted in significantly enhanced inhibition of Sk-Hep1, Huh7, and HepG2 CSC viability.

In summary, the studies described in Examples 1 and 2 demonstrate that Compound A and Compound C have a synergistic effect in vitro, and these data indicate the significant potential for combined treatment of HCC using Compound A and Compound C.

Example 3: Treatment of human cancer xenograft model with compound A (BBI608)

In a mouse xenograft model of human HCC, HepG2 cells were subcutaneously inoculated into male athymic nude mice (8 × 10 ⁶ cells / mouse) and formed a palpable tumor. Once the tumor reached approximately 500 mm ³ , the animals were treated orally with the vehicle (control group) or Compound A (BBI608; 10 mg / kg, iv) as shown in FIG. 3. Animals received a total of 5 doses. Compared with control animals, treatment with Compound A (BBI608) inhibited tumor growth.

Example 4: Combination treatment with Compound B (BBI503) and Compound C (Sorafenib) enhances the inhibition of the formation of large numbers of cancer cell colonies in vitro

The colony formation assay was used to examine the ability of a large number of cancer cells to undergo pure strain expansion after combined treatment with Compound B (BBI503) and Compound C (Sorafenib). For these studies, human HCC cell lines (Hep3B and Hub7, 1000 cells / well) were seeded in 6-well dishes. 24 hours after inoculation, cells were treated with DMSO (control group), Compound B alone (0.3 μM), Compound C alone (2 μM) or a combination of Compound B (0.3 μM) and Compound C (2 μM). The cells are then cultured for 7-10 days until the visible colonies are formed.

As shown in Figures 4 and 5, the combined treatment with Compound B (BBI503) and Compound C (Sorafenib) is compared to the treatment with Compound B (BBI503) alone or Compound C (Sorafenib) alone This results in enhanced inhibition of HCC community formation.

Example 5: Combination therapy with Compound B (BBI503) and Compound C (Sorafenib) enhances inhibition of cancer stem cell spheroids formation in vitro

After treating cancer cells with a combination of Compound B (BBI503) and Compound C (Sorafenib) ("combo"), cancer stem cell spheroids formation (ie, spherogenesis) was examined. Sk-Hep1, Huh7, and HepG2 cells alone were grown in suspension for 48 hours, and then compound B (BBI503; 1 μM), compound C (Sorafenib; 2 μM), or compound alone at concentrations of 1 μM and 2 μM, respectively. The combination of B (BBI503) and Compound C (Sorafenib) was cultured for 24 hours in the presence of. The cells were then washed and incubated in standard cell culture medium for another 24 hours. Then use The interference phase contrast (DIC) microscope inspects the cells and takes pictures. As Tryphan Blue stains the cells blue, it indicates the presence of dead cells.

As shown in Figure 6, treatment with a combination of Compound B (BBI503) and Compound C (Sorafenib) ("combo") compared to Compound B (BBI503) alone or Compound C (Sorafenib) alone Treatment resulted in a significant increase in the inhibition of Sk-Hep1, Huh7, and HepG2 CSC viability.

In summary, the studies described in Examples 4 and 5 demonstrate that Compound B and Compound C have a synergistic effect in vitro, and these data indicate the significant potential for combined treatment of HCC using Compound B and Compound C.

Example 6: Treatment of a human cancer xenograft model with Compound B (BBI503)

In a mouse xenograft model of human HCC, HepG2 cells were subcutaneously inoculated into male athymic nude mice (8 × 10 ⁶ cells / mouse) and formed a palpable tumor. Once the tumor reached about 500 mm ³ , the animals were treated orally with the vehicle (control group) or Compound B (BBI503; 100 mg / kg, po) as shown in FIG. 7. Animals received a total of 5 doses. Compared with control animals, treatment with Compound B (BBI503) inhibited tumor growth.

Example 7: Clinical trial of combined treatment of Compound A (BBI608) and Compound C (Sorafenib) or Compound B (BBI503) and Compound C (Sorafenib)

The efficacy of the two combination therapies in patients with advanced hepatocellular carcinoma was studied in a phase IB / II study to evaluate the safety, tolerability, and preliminary anticancer activity of the drug combination disclosed herein. The first combination therapy includes Compound A (BBI608) and Compound C (Sorafenib), and the second combination therapy includes Compound B (BBI503) and Compound C (Sorafenib).

This open label, IB / II study identified the above drug combination The safety and effectiveness of the group of patients with advanced hepatocellular carcinoma who have not yet received systemic chemotherapy. The Phase IB part involves the administration of increasing doses of Compound A (BBI608) (Group 1) in combination with a fixed starting dose of Compound C (Sorafenib) and Compound B (BBI503) in combination with a fixed starting dose Increasing compound C (Sorafenib) (Group 2). The fixed starting dose level of sorafenib in both groups was 400 mg twice daily (800 mg total daily dose). Eligible patients were randomly assigned to 1 or 2 groups.

In Group 1, dose-escalating Compound A (BBI608) was administered to a cohort of three to six patients until the recommended Phase II dose (RP2D) was determined based on established criteria for determining dose-limiting toxicity (DLT) and dose escalation .

In Group 2, dose-escalating Compound B (BBI503) was administered to a cohort of three to six patients until the recommended Phase II dose (RP2D) was determined based on established criteria for determining dose-limiting toxicity (DLT) and dose escalation .

Before each group started combination therapy, compound C (sorafenib) was administered as a single treatment, starting from cycle 1, 14 days from the first day. Adjust the dose of sorafenib according to the approved product label. After the sorafenib run-in period, the combined regimen starts on week 1, day 15. The regimen continues to repeat a 28-day cycle until it meets disease progression, unacceptable toxicity, or other withdrawal criteria.

For both groups, pharmacokinetic (PK) studies were conducted on cycle 1, day 15, and week 2, day 15. Pharmacokinetic studies were also conducted as needed to confirm dose-exposure exposure. Once the recommended phase II dose (RP2D) of the two study groups was established, the phase II part was started.

The phase II part is an open-label, three-group randomized phase II trial of advanced HCC patients who have not received systemic treatment. Patients were randomly assigned to receive 1 group: Compound C (Sola Fini) administered in combination with Compound A (BBI608) (with BRP608 plus RP2D confirmed by Sorafenib during part of phase IB); Group 2: combination of Compound C (Sorafenib) and Compound B (BBI503) (Adding RP2D confirmed by sorafenib to BBI503 during part of phase IB), or 3 groups: Compound C alone (sorafenib), starting at 400 mg twice daily. The starting dose of sorafenib was the same in all study groups.

A total of approximately 90 patients participated in the phase II portion of the study, or approximately 30 patients per study group.

With the optional research tumor biopsy, the drug efficacy of patients with easy access to tumors is evaluated. Collect filing organizations (if any) from all patients.

Throughout the study, the safety and tolerability of the combination of Compound A (BBI608) and Compound C (Sorafenib) and the combination of Compound B (BBI503) and Compound C (Sorafenib) during the study treatment were continuously evaluated Sex, and continued for up to 30 days after stopping the study drug (Compound A or Compound B).

The anti-tumor activity was evaluated in 8 routine weeks, and the first evaluation was performed 8 weeks (56 days) after the first day of the first cycle. According to RECIST 1.1 and the revised RECIST (mRECIST), radiological assessment was performed on HCC patients. Alpha fetoprotein (AFP) measurements at baseline were performed at the end of the 2-week sorafenib monotherapy introduction period and at the beginning of each subsequent study period.

As long as the patient obtains potential clinical benefit under the opinion of the investigator, let the patient continue the treatment plan, exceeding the progress determined by the RECIST standard (RECIST1.1 or mRECIST for HCC patients). If sorafenib is discontinued due to sorafenib-related toxicity, the patient is allowed to continue to receive the study drug (BBI608 or BBI503), provided there are no signs of toxicity and the patient has received Have clinical benefits.

Patient characteristics

Combined solution security

Pharmacokinetics

Of the 17 patients evaluated by RECIST, 9 were in group 1 and 8 in group 2. DCR was observed in 100% of the assessable patients in groups 1 and 2, 9SD in group 1, and 8SD in group 2. RECIST for napabuxin + sorafenib and acaxicin + sorafenib The preliminary results of 1.1 and mRECIST are shown in Figures 8A and 8B, respectively.

Napabuxin and acarbamicin are safely combined with full-dose sorafenib without accidental adverse events. Exciting anticancer activity was observed in HCC patients who have not received systemic treatment. The RP2D dose was determined to be 240 mg BID for napabuxin and 100 mg QD for acarbamicin. The randomized phase II portion of this study is currently recruiting patients into three groups. Group I: napabuxin + sorafenib, group II: acarbamicin + sorafenib and group III: sorafenib alone.

Many of the features and advantages of the disclosure of this document are apparent from the detailed description, and therefore the scope of the accompanying patent application is intended to cover all such features and advantages of the disclosure of this document that fall within the true spirit and scope of the disclosure of this document. In addition, since many modifications and changes can easily occur to those with ordinary knowledge in the technical field, it is undesirable to limit the disclosure of this document to the precise construction and operation illustrated and described. Therefore, all suitable modifications and equivalents can be resorted to, which are within the scope of the disclosure of this article.

Figure 1 illustrates the enhanced inhibition of HCC colony formation by Hep3B cell line after treatment of cells using a combination of compounds of formula A and formula C.

Figure 2 shows an example of enhanced inhibition of Sk-Hep1, Huh7, and HepG2 CSC viability after treatment of cells using a combination of a compound of formula A and a compound of formula C.

Figure 3 shows an example of inhibiting tumor growth in a HCC xenograft mouse model after treatment with a compound of formula A.

Figure 4 illustrates the enhanced inhibition of HCC colony formation by Hep3B cell line after treatment of cells using a combination of compounds of formula B and compound of formula C.

Figure 5 illustrates the enhanced inhibition of HCC colony formation by the Hub7 cell line after treatment of cells using a combination of the compound of formula B and the compound of formula C.

Fig. 6 shows an example of enhancing the inhibition of the viability of Skhep1, Hep3B, and HepG2 CSC after treating cells with a combination of the compound of formula B and the compound of formula C.

Figure 7 shows an example of inhibiting tumor growth in a HCC xenograft mouse model after treatment with a compound of formula B.

Figure 8A shows the evaluation of advanced HCC patients treated with napabucasin (BBI608, compound A) and sorafenib (compound C) according to RECIST 1.1 and modified RECIST (mRECIST).

Figure 8B shows the evaluation of patients with advanced HCC treated with acarbamicin (amcasertib) (BBC503, Compound B) and sorafenib (Compound C) according to RECIST 1.1 and modified RECIST (mRECIST).

Claims (34)

A method for treating cancer in an individual in need thereof, comprising administering: (a) a therapeutically effective amount of at least one first compound selected from cancer stemness inhibitors, prodrugs thereof, and Derivatives, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing; and (b) a therapeutically effective amount of at least one second compound selected from the group consisting of kinase inhibitors and prodrugs thereof , Derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. A method for treating cancer that is refractory or resistant to a kinase inhibitor in an individual, which comprises administering: (a) a therapeutically effective amount of at least one first compound selected from cancer stem inhibitors, A prodrug, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing; and (b) a therapeutically effective amount of at least one second compound selected from kinase inhibition Agents, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. A method for preventing the recurrence of cancer in an individual, comprising administering: (a) a therapeutically effective amount of at least one first compound selected from the group consisting of cancer stem inhibitors, prodrugs, derivatives thereof, and any of the foregoing Acceptable salts, and solvates of any of the foregoing; and (b) a therapeutically effective amount of at least one second compound selected from the group consisting of kinase inhibitors, prodrugs, derivatives thereof, and any of the foregoing Pharmaceutically acceptable salts, and any of the foregoing Solvate. A method for inhibiting cancer regrowth or recurrence in an individual, comprising administering: (a) a therapeutically effective amount of at least one first compound selected from cancer stem inhibitors, prodrugs, derivatives thereof, any of the foregoing A pharmaceutically acceptable salt of the above, and a solvate of any of the foregoing; and (b) a therapeutically effective amount of at least one second compound selected from the group consisting of kinase inhibitors, prodrugs, derivatives thereof, the foregoing A pharmaceutically acceptable salt of any one, and a solvate of any of the foregoing. The method according to any one of items 1 to 4 of the patent application range, wherein the cancer stemness inhibitor comprises a STAT3 pathway inhibitor. The method according to any one of items 1 to 5 of the patent application range, wherein the cancer desiccant inhibitor comprises 2- (1-hydroxyethyl) -naphtho [2,3- b ] furan-4,9-di Ketones, 2-aceto-7-chloro-naphtho [2,3- b ] furan-4,9-dione, 2-aceto-7-fluoro-naphtho [2,3- b ] furan -4,9-dione, 2-acetonaphtho [2,3- b ] furan-4,9-dione, and 2-ethyl-naphtho [2,3- b ] furan-4, 9-diketone. The method according to any one of claims 1 to 6, wherein the cancer stemness inhibitor comprises a compound having formula A: The method according to any one of items 1 to 7 of the patent application range, wherein the cancer stemness inhibitor comprises at least one inhibitor selected from cancer stem cell pathway kinase (CSCPK) kinases. The method according to item 8 of the patent application range, wherein the at least one kinase system is selected from STK33, MELK, AXL, p70S6K, and PDGFR α. The method according to any one of items 1 to 9 of the patent application range, wherein the cancer stem suppressant comprises ,as well as The method according to any one of claims 1 to 10, wherein the cancer stemness inhibitor comprises a compound of formula B: The method according to any one of items 1 to 11 of the patent application range, wherein the kinase inhibitor comprises a compound having the formula C: The method according to any one of claims 1 to 12, wherein the cancer is selected from liver cancer. The method according to any one of claims 1 to 13, wherein the cancer is selected from hepatocellular carcinoma and cholangiocarcinoma. The method according to any one of items 1 to 14 of the patent application range, wherein the cancer is advanced, refractory, relapsed, or metastatic. A method for sensitizing or resensitizing cancer cells to kinase inhibitors, comprising administering to the cancer cells at least one first compound selected from cancer stem inhibitors, prodrugs, derivatives thereof, the foregoing Any of the pharmaceutically acceptable salts, and any of the foregoing Solvate. A method for treating cancer cells, which comprises administering a therapeutically effective amount of at least one first compound selected from cancer dryness inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceuticals of any of the foregoing Acceptable salts, and solvates of any of the foregoing. The method according to any one of claims 16 to 17, wherein the cancer cell line is within the individual. The method according to any one of claims 16 to 18, wherein the cancer stemness inhibitor comprises a STAT3 pathway inhibitor. The method according to any one of claims 16 to 19, wherein the cancer desiccant inhibitor comprises 2- (1-hydroxyethyl) -naphtho [2,3- b ] furan-4,9-di Ketones, 2-aceto-7-chloro-naphtho [2,3- b ] furan-4,9-dione, 2-aceto-7-fluoro-naphtho [2,3- b ] furan -4,9-dione, 2-acetonaphtho [2,3- b ] furan-4,9-dione, and 2-ethyl-naphtho [2,3- b ] furan-4, 9-diketone. The method according to any one of claims 16 to 20, wherein the cancer stemness inhibitor comprises a compound having formula A: The method according to any one of claims 16 to 18, wherein the cancer stemness inhibitor comprises a cancer stem cell pathway inhibitor. The method according to any one of claims 16 to 18 and 22, wherein the cancer ,as well as The method according to any one of claims 16 to 18, 22, and 23, wherein the cancer stemness inhibitor comprises a compound having formula B: The method according to any one of claims 16 to 23, which comprises administering a therapeutically effective amount of at least one second compound selected from the group consisting of kinase inhibitors, prodrugs, derivatives thereof, and any of the foregoing Pharmaceutically acceptable salts and solvates of any of the foregoing. The method according to any one of claims 16 to 25, wherein the kinase inhibitor comprises a compound of formula C: The method according to any one of items 16 to 26 of the patent application range, wherein the cancer is selected from liver cancer. The method according to any one of claims 16 to 27, wherein the cancer is selected from hepatocellular carcinoma and cholangiocarcinoma. The method according to any one of claims 16 to 28, wherein the cancer is advanced, refractory, relapsed, or metastatic. A method for treating cancer in an individual, comprising administering to an individual in need a therapeutically effective amount of at least one first compound selected from compounds having formula A: And compounds of formula B: A prodrug, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing; and a therapeutically effective amount of at least one second compound selected from compounds having formula C : Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. A method for treating cancer that is refractory or resistant to at least one kinase inhibitor in an individual, which comprises administering to the individual in need thereof a therapeutically effective amount of at least one first compound selected from formula A compound of: And compounds of formula B: A prodrug, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing; and a therapeutically effective amount of at least one second compound selected from compounds having formula C : Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. A method of sensitizing cancer to at least one kinase inhibitor in an individual, which comprises administering to a subject in need thereof a therapeutically effective amount of at least one first compound selected from compounds having formula A: And compounds of formula B: Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. A method for resensitizing cancer to at least one kinase inhibitor in an individual, which comprises administering to the individual in need thereof a therapeutically effective amount of at least one first compound selected from compounds having formula A: And compounds of formula B: Prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. A kit comprising (a) at least one first compound selected from cancer dryness inhibitors, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and any of the foregoing Solvate; (b) at least one second compound selected from the group consisting of kinase inhibitors, prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing Substances; and (c) guidelines for administration and / or use of the at least one first compound and the at least one second compound.