Methods of Treating Cancer Using HSF1 Pathway Inhibitors

Abstract

This disclosure is directed in part to a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of an HSF1 pathway inhibitor, wherein the cancer consists of a solid tumor identified as having an ARID1A mutation.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 252,657, filed October 6, 2021, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Cancer is caused by uncontrolled and unregulated cell proliferation. What causes cells to become malignant and proliferate in an uncontrolled and unregulated manner has been the subject of intense research over the past few decades. This research has led to the identification of numerous molecular targets related to major metabolic pathways known to be associated with malignant tumors.

[0003] The heat shock factor 1 pathway (HSF1 pathway) is one of the target pathways of interest. HSF1 is a master regulator of the heat shock response, in which multiple genes are induced in response to elevated temperature and other stresses. At non-shock temperatures in humans and other vertebrates, HSF1 is constitutively produced but inactive and bound to the protein HSP90. Upon temperature increase, HSF1 is released by HSP90, translocates from the cytoplasm to the nucleus, and trimerizes. This active form of HSF1 binds to sequences in DNA called heat shock elements (HSEs) and activates the transcription of heat shock genes by RNA polymerase II. When the heat shock response is terminated, HSF1 is phosphorylated by mitogen-activated protein kinases (MAPKs) and glycogen synthase kinase 3 (GSK3) and returns to its inactive state.

[0004] The activity of the HSF1 pathway is involved in several diseases, such as cancer, autoimmune diseases, and viral diseases. HSF1 and other heat shock proteins (whose expression is increased by HSF1) are overexpressed or otherwise involved in breast cancer, endometrial cancer, fibrosarcoma, gastric cancer, renal cancer, liver cancer, lung cancer, lymphoma, neuroectodermal cancer, neuroblastoma, Ewing's sarcoma, prostate cancer, skin cancer, squamous cell carcinoma, testicular cancer, leukemia (e.g., promyelocytic leukemia), and Hodgkin's disease.

[0005] ARID1A is a member of the SWI / SNF family, whose members have helicase and ATPase activities and are thought to regulate the transcription of specific genes by altering the chromatin structure surrounding the genes. ARID1A regulates the expression of key components of metabolic pathways that enhance the survival of cancer cells by promoting the production of glutathione (GSH) and protecting them from metabolic stress induced by reactive oxygen species (ROS).

[0006] ARID1A is mutated in multiple solid tumor types with varying frequency. For example, ARID1A mutations are common in cancers and solid tumor types, including breast, lung, esophageal, pancreatic, urothelial, uterine, ovarian, gastrointestinal, and liver cancers. ARID1A mutations are associated with cell cycle abnormalities that lead to reduced GSH levels, resulting in reduced defense against stress. Cancer cells compensate by overactivating the HSF-1 pathway.

[0007] Loss of protein associated with ARID1A mutation can be used as a patient selection strategy in solid tumor types.Methodology for detecting ARID1A mutation is known in the art.Therefore, there is a need for a method for treating diseases or conditions mediated by HSF1 pathway activity, such as cancer that manifests as solid tumors with ARID1A1a mutation. Summary of the Invention [Means for solving the problem]

[0008] The present disclosure is directed, at least in part, to a method of treating cancer with a compound that regulates, for example, inhibits, HSF1 pathway.For example, disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of an HSF1 pathway inhibitor, wherein the cancer comprises a solid tumor carrying ARID1A mutation, for example, a solid tumor that is identified as having ARID1A mutation.In some embodiments, the cancer can be selected from the group consisting of, for example, ovarian cancer, gastric cancer and pancreatic cancer.

[0009] Further disclosed herein is a method for treating ovarian cancer in a patient in need thereof, comprising administering to the patient an effective amount of an HSF1 pathway inhibitor, wherein the cancer comprises a solid tumor carrying an ARID1A mutation, for example, a solid tumor identified as having an ARID1A mutation. In some embodiments, the ovarian cancer is, for example, an endometrioid ovarian cancer or an ovarian clear cell carcinoma.

[0010] In some embodiments, the HSF1 pathway inhibitor is, for example, N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide)-2-fluorophenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide, represented by the following: JPEG2024536446000002.jpg3091

[0011] For example, disclosed herein is a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient an effective amount of N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide, or a pharma- ceutically acceptable salt thereof, wherein the cancer comprises a solid tumor harboring an ARID1A mutation. [Brief description of the drawings]

[0012] [Figure 1]Figure 1 shows the antitumor activity (e.g., tumor growth inhibition) of Compound A in an ovarian cancer xenograft model (SKOV-3). The tumor was identified as having an ARID1A mutation. Cr nude mice were injected with 5x106 SK-OV-3 cells, and after tumor formation, vehicle control (DCC) or Compound A in DCC was orally administered 35mg / kg once daily (or as described in the text). The graph shows the average tumor volume during the treatment period, and the error bars show the standard error of the mean. n=10 for control and 35mg / kg group. The horizontal black line is the tumor volume of the 35mg / kg group on day 0 of treatment.

[0013] [Diagram 2] Figure 1 shows the antitumor activity (e.g., tumor growth inhibition) of Compound A in an ovarian cancer xenograft model (TOV-21G). The tumor was identified as having an ARID1A mutation. NCr nude mice were injected with 3x106 TOV-21G cells, and after tumor formation, they were orally administered vehicle control (DCC) or Compound A in DCC at 35mg / kg once a day for 5 days out of every 7 days. The graph shows the average tumor volume during the treatment period, and the error bars show the standard error of the mean. Vehicle control group n=8, 35mg / kg treatment group n=11.

[0014] [Diagram 3] The antitumor activity (e.g., tumor growth inhibition) of compound A in ovarian cancer xenograft model (OVISE) is shown. 5x106 OVISE cells are injected into NCr nude mice, and after tumor formation, vehicle control (DCC) or compound A in DCC is orally administered 35mg / kg once a day for 5 days out of every 7 days. The graph shows the average tumor volume during the administration period, and the error bar shows the standard error of the mean. Vehicle control group n=10, 35mg / kg compound A group n=11.

[0015] [Figure 4]The antitumor activity (e.g., tumor growth inhibition) of compound A in ovarian cancer xenograft model (IGROV-1) is shown. NCr nude mice are injected with 3x106 IGROV-1 cells, and after tumor formation, vehicle control (DCC) or compound A 35mg / kg in DCC is orally administered once a day on an intermittent schedule. The graph shows the average tumor volume during the administration period, and the error bar shows the standard error of the mean. Vehicle control group n=5, 35mg / kg compound A group n=6.

[0016] [Diagram 5] An outline of tumor xenograft experiments is shown. Formed tumor xenografts were treated (compound A at 35 mg / kg oral schedule once daily as shown in Table 1). TGI>50% was considered significant and indicated by dotted line. All experiments were performed with at least n=9 control and treated mice (except IGROV-1, n=6 treated and n=5 control). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The features and other details of the present disclosure are described in more detail below.Before further description of the present disclosure, the specific terms employed in the present specification, examples and appended claims are collected here.These definitions should be read in the light of the remaining parts of the present disclosure as understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0018] definition "Treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., e.g., alleviation, reduction, modulation, or elimination. For example, "treating" or "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the appearance of clinical symptoms of an existing condition, disorder, or condition in a human suffering from or predisposed to suffering from the condition, disorder, or condition, but who has not yet experienced or manifested a clinical or subclinical symptom of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the recurrence of the disease (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof; or (3) relieving or attenuating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof. It is understood that "treating" or "treatment" includes prevention as well as alleviation of established symptoms.

[0019] The term "disorder" refers to, and is used interchangeably with, the terms "disease," "symptom," and "illness," unless otherwise noted.

[0020] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to animals or humans. For human administration, preparations should meet the sterility, pyrogenicity, general safety and purity standards required by the FDA Office of Biologics.

[0021] "Individual", "patient" or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans. The compounds of the present disclosure can be administered to mammals, such as humans, but also to other mammals, such as animals requiring veterinary treatment, for example, livestock animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammals treated in the methods of the present disclosure are desirably mammals in which treatment of, for example, cancer or blood disorders is desired. "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0022] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of interest that elicits a biological or medical response in a tissue, system or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, medical doctor or other clinician. The compounds of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve a desired therapeutic and / or prophylactic effect.

[0023] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts of basic groups that may be present in the compounds used in the compositions. Compounds contained in the compositions that are basic can form a wide variety of salts with various inorganic and organic acids.

[0024] In this disclosure, the term "and / or" means either "and" or "or," unless otherwise stated.

[0025] As used herein, the terms "a" and "an" are meant to include one or more, unless otherwise specified. For example, the term "agent" includes both a single agent and a combination of two or more agents.

[0026] When the term "about" is used before a quantitative value, the disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise indicated or inferred.

[0027] method In some embodiments, disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of an HSF1 pathway inhibitor, wherein the cancer consists of a solid tumor harboring an ARID1A mutation.

[0028] For example, in some embodiments, the cancer is selected from the group consisting of, for example, ovarian cancer, gastric cancer and pancreatic cancer. In certain embodiments, the cancer is endometrioid ovarian cancer, for example, the cancer is recurrent or refractory endometrioid ovarian cancer. In other embodiments, the cancer is ovarian clear cell carcinoma. In some embodiments, the cancer is recurrent or refractory ovarian clear cell carcinoma. In certain embodiments, the ovarian cancer is substantially resistant to platinum-based chemotherapy, taxane-based chemotherapy or a combination thereof.

[0029] In some embodiments, the HSF1 pathway inhibitor is, for example, the following compound or a pharma- ceutically acceptable salt thereof: JPEG2024536446000003.jpg3091

[0030] For example, in certain embodiments, the HSF1 pathway inhibitor is the following compound: JPEG2024536446000004.jpg3091

[0031] In some embodiments, the ARID1A mutation is a heterozygous ARID1A mutation. In other embodiments, the ARID1A mutation is a homozygous ARID1A mutation.

[0032] In further embodiments, the HSF1 pathway inhibitor is administered orally or subcutaneously. In some embodiments, administration reduces, for example, the mean GI 50 In other embodiments, the administration results in about a 2- to 5-fold decrease in the mean GI in ARID1A mutant ovarian cancer cells, for example, compared to wild-type ARID1A ovarian cells. 50 This results in an approximately four- to five-fold reduction in

[0033] In some embodiments, the method optionally further comprises administering one or more additional cancer chemotherapeutic agents. For example, in other embodiments, the method optionally further comprises administering an additional cancer chemotherapeutic agent.

[0034] Also disclosed herein is a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient an effective amount of an HSF1 pathway inhibitor, wherein the cancer comprises a solid tumor carrying an ARID1A mutation. In certain embodiments, the cancer is endometrioid ovarian cancer, e.g., the cancer is recurrent or refractory endometrioid ovarian cancer. In other embodiments, the cancer is ovarian clear cell carcinoma. In some embodiments, the cancer is recurrent or refractory ovarian clear cell carcinoma. In certain embodiments, the HSF1 pathway inhibitor is the following compound or a pharmaceutically acceptable salt thereof: JPEG2024536446000005.jpg3091

[0035] Further disclosed herein is a method for treating ovarian cancer in a patient in need thereof, comprising administering to the patient an effective amount of an HSF1 pathway inhibitor represented by the following compound, or a pharma- ceutically acceptable salt thereof: JPEG2024536446000006.jpg3091, wherein the cancer comprises a solid tumor carrying an ARID1A mutation. In some embodiments, the ovarian cancer is, for example, endometrioid ovarian cancer or ovarian clear cell carcinoma.

[0036] In some embodiments, the cancer or solid tumor disclosed herein is identified as having ARID1A mutation.The methodology for detecting ARID1A mutation is known in the art.For example, the protein loss associated with ARID1A mutation can be used as a patient selection strategy in solid tumors.

[0037] In particular, in certain embodiments, the present disclosure provides a method of treating the above medical indications comprising administering to a patient in need thereof an effective amount of an HSF1 pathway inhibitor disclosed herein. In certain other embodiments, the present disclosure provides a method of treating the above medical indications in a patient in need thereof comprising administering to the patient orally, subcutaneously or intravenously a composition comprising a disclosed HSF1 pathway inhibitor.

[0038] In some embodiments, the therapeutic methods disclosed herein may provide an anti-proliferative effect. In some embodiments, the therapeutic methods disclosed herein may be methods of treating a proliferative disease or disorder. The terms "proliferative disease" and "proliferative disorder" are used interchangeably herein and relate to unwanted or uncontrolled cell proliferation of unwanted excess or abnormal cells, such as neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include pre-malignant and malignant cell proliferation, including but not limited to cancer and solid tumors. Any type of cell may be treated, including but not limited to lung, liver, stomach, colon, breast, ovary, prostate, liver, pancreas, brain, skin, etc.

[0039] The anti-proliferative effects of the methods disclosed herein have particular application in the treatment of human cancers due to their HSF1 inhibitory properties. Anti-cancer effects may occur through one or more mechanisms, including but not limited to regulating cell proliferation, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of tumors from their origin), inhibiting invasion (the spread of tumor cells to nearby normal structures), or promoting apoptosis (programmed cell death). Anti-proliferative and anti-cancer effects are observed in cancers and solid tumor types identified as having ARID1A mutations.

[0040] The therapeutic methods defined herein can be applied as monotherapy or can be combined with conventional surgery, radiation therapy, gene therapy, or chemotherapy or molecular targeted drug therapy in addition to the compounds of the present invention. Such combined treatment can be achieved by simultaneous, sequential or separate administration of the individual components of the treatment. The term "combination" as used herein means simultaneous, separate or sequential administration. In some embodiments, "combination" refers to simultaneous administration. In other embodiments, "combination" refers to separate administration. In further embodiments, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such as to lose the beneficial effect of the combination. EXAMPLES

[0041] The following non-limiting examples illustrate the present disclosure.

[0042] N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide)-2-fluorophenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide (Compound A) can be prepared according to the synthetic procedures of WO2015 / 049535, which is incorporated herein by reference.

[0043] In vivo efficacy testing The in vivo efficacy of compound A was investigated in xenograft tumors in athymic nude mice, mainly ovarian cancer. The efficacy of compound A was examined in xenograft mice using the following ovarian cancer cell lines: SK-OV-3, TOV-21G, OVISE, IGROV1, OVCAR-5, ES-2, and RMG1. Of the seven cell lines, SK-OV-3, TOV-21G, OVISE, and IGROV1 harbored ARID1A mutations, while OVCAR-5, ES-2, and RMG1 were ARID1A wild type.

[0044] Once tumors had formed, mice were randomly assigned to vehicle control and treatment groups. Mice in both vehicle control and treatment groups that were removed during the course of the study due to spontaneous or treatment-induced tumor regression, tumor growth approaching acceptable limits, tumor ulceration, or loss of symptoms were excluded from the final analysis of mean tumor volume and standard error of the mean up to the time of removal from the study. The number of mice in the treatment groups with complete tumor regression was reported where applicable.

[0045] Two groups of 12 female NCr nude mice (SK-OV-3: 10 mice × 3 groups) were inoculated with 3–5 × 10 cells from one of the above cancer cell lines. 6 Cells were injected subcutaneously. Once tumors reached this size, groups were orally dosed once daily with vehicle control (10% DMSO, 25% 2-hydroxypropyl-β-cyclodextrin in 90% of 50 mM sodium citrate buffer pH 5 [DCC]) or compound A at 35 or 70 mg / kg, DCC. Body weights were measured daily and animals were monitored for signs of toxicity. To assess drug levels, animals were euthanized in batches of 3–4 at 2, 6, and 24 h after the last dose, and terminal plasma and tumor samples were collected for PK analysis. Differences in final tumor volumes (p<0.005, Mann-Whitney test) between the compound A-treated group and the control group were recorded. The results are shown in Table 1. Table 1: Compound A 35 mg / kg administration schedule and details of TGI obtained in the study [Table 1]

[0046] Figures 1, 2, 3 and 4 show the anti-tumor activity (e.g., tumor growth inhibition) of Compound A in ovarian clear cell carcinoma xenograft models: SKOV-3, TOV-21G, OVISE and IGROV1 (each identified as harboring an ARID1A mutation).

[0047] As shown in Table 1, a slight efficacy signal was observed in the ARID1A wild-type OVCAR-5 and ES-2 models (%TGI 27% and 12%, respectively), which did not meet the efficacy criteria (%TGI .50%). No inhibition of xenograft tumor growth was observed in the ARID1A wild-type RMG1 model. Plasma C in the OVCAR-5 and ES-2 models max was within the range observed in efficacy studies, but plasma C max was less than half the lowest level seen in efficacy trials. The SK-OV-3 ovarian cancer cell line, which harbors an ARID1A mutation, was the most sensitive cell line in the xenograft model.

[0048] 5 is a comparative graph of the antitumor activity (e.g., tumor growth inhibition) of Compound A in seven ovarian cancer xenograft models examined: SK-OV-3; TOV-21G, OVISE, IGROV1, OVCAR-5, ES-2, and RMG1.

[0049] Incorporation by Reference All publications and patents mentioned herein, including those listed below, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the case of conflict, the present application, including definitions herein, will control. Equivalent Although specific embodiments of the present disclosure have been described, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the present disclosure, together with such variations, together with the full scope of equivalents, should be determined by reference to the claims and the specification. Unless otherwise indicated, all numerical values ​​expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are understood to be modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. A pharmaceutical composition for treating cancer, including solid tumors harboring an ARID1A mutation, comprising an effective amount of an HSF1 pathway inhibitor.

2. 2. The pharmaceutical composition according to claim 1, wherein the cancer is selected from the group consisting of ovarian cancer, gastric cancer, and pancreatic cancer.

3. 3. The pharmaceutical composition according to claim 1, wherein the cancer is endometrioid ovarian cancer.

4. 3. The pharmaceutical composition according to claim 1, wherein the cancer is recurrent or refractory endometrioid ovarian cancer.

5. The pharmaceutical composition according to claim 1 or 2, wherein the cancer is ovarian clear cell carcinoma.

6. The pharmaceutical composition according to claim 5, wherein the cancer is recurrent or refractory ovarian clear cell carcinoma.

7. The pharmaceutical composition according to claim 2, wherein the ovarian cancer is substantially resistant to platinum-based chemotherapy, taxane-based chemotherapy, or a combination thereof.

8. 3. The pharmaceutical composition according to claim 1, wherein the HSF1 pathway inhibitor is the following compound or a pharmaceutically acceptable salt thereof:

9. The pharmaceutical composition according to claim 1 or 2, wherein the HSF1 pathway inhibitor is the following compound:

10. The pharmaceutical composition according to claim 1 or 2, wherein the ARID1A mutation is a heterozygous ARID1A mutation.

11. The pharmaceutical composition according to claim 1 or 2, wherein the ARID1A mutation is a homozygous ARID1A mutation.

12. The pharmaceutical composition according to claim 1 or 2, for oral or subcutaneous administration of the HSF1 pathway inhibitor.

13. Administration of ARID1A mutant cancer cells ５０ The pharmaceutical composition according to claim 1 or 2, wherein the activity of ARID1A in the ARID1A-positive cells is reduced by about 2 to 5 times compared to that in wild-type ARID1A cells.

14. Administration of ARID1A mutant ovarian cancer cells ５０ The pharmaceutical composition according to claim 1 or 2, wherein the expression level of ARID1A in ovarian cancer cells is reduced by about 4 to 5 times compared to wild-type ARID1A cells.

15. The pharmaceutical composition according to claim 1 or 2, further optionally comprising one or more additional cancer chemotherapeutic agents in combination.

16. 3. The pharmaceutical composition of claim 1 or 2, further optionally comprising an additional cancer chemotherapeutic agent.

17. A pharmaceutical composition for treating ovarian cancer, including solid tumors harboring ARID1A mutations, comprising an effective amount of an HSF1 pathway inhibitor.

18. The pharmaceutical composition according to claim 17, wherein the ovarian cancer is endometrioid ovarian cancer.

19. The pharmaceutical composition according to claim 17 or 18, wherein the cancer is recurrent or refractory endometrioid ovarian cancer.

20. The pharmaceutical composition according to claim 17, wherein the cancer is ovarian clear cell carcinoma.

21. The pharmaceutical composition according to claim 17 or 20, wherein the cancer is recurrent or refractory ovarian clear cell carcinoma.

22. 18. The pharmaceutical composition of claim 17, wherein the HSF1 pathway inhibitor is the following compound or a pharmaceutically acceptable salt thereof:

23. A pharmaceutical composition for treating ovarian cancer, including solid tumors harboring an ARID1A mutation, comprising an effective amount of an HSF1 pathway inhibitor represented by the following formula or a pharmaceutically acceptable salt thereof:

24. The pharmaceutical composition according to claim 23, wherein the ovarian cancer is endometrioid ovarian cancer or ovarian clear cell carcinoma.

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