Methods of Treating Prostate Cancer

Abstract

The present invention generally relates to a method of treating prostate cancer with a substituted tricyclic derivative, 2-[3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol, or a pharma- ceutically acceptable salt thereof, as a bromodomain inhibitor.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority pursuant to 35 USC § 119(e) to U.S. Provisional Application No. 63 / 160,319, filed March 12, 2021, which is incorporated herein in its entirety.

[0002] Field The present application relates generally to compositions and methods for treating prostate cancer with substituted heterocyclic derivative compounds or pharma- ceutically acceptable salts thereof as bromodomain inhibitors. [Background technology]

[0003] background Prostate cancer is the second leading cause of cancer-related death in men and the most commonly diagnosed cancer. Prostate cancer tumors consist primarily of prostate luminal epithelial cells. Differentiation of prostate luminal epithelial cells is controlled, in part, by androgen receptor (AR)-driven expression of prostate-specific markers. AR is a steroid receptor that functions as a transcription factor and controls cell survival through mechanisms that remain unknown. Androgen deprivation causes normal prostate luminal epithelial cells to die, indicating a critical role for the AR pathway in their survival. Cancerous prostate cells continue to express AR, and their survival is also dependent on the presence of androgens, making androgen deprivation a common treatment for patients with advanced prostate cancer. First-line treatment of prostate cancer aims to reduce circulating androgen levels via androgen deprivation therapy (ADT). Although ADT is initially effective in reducing prostate cancer growth, after 2–3 years of treatment, the majority of patients progress to castration-resistant prostate cancer (CRPC), where tumor growth progresses even in the presence of only castration levels of androgen. At this point in the disease progression, the number of treatment options becomes extremely limited. Summary of the Invention [Problem to be solved by the invention]

[0004] Thus, there is a need for more effective treatments for prostate cancer, which the present invention meets. [Means for solving the problem]

[0005] overview The present invention relates generally to compositions and methods for treating prostate cancer. The methods include administering a therapeutically effective amount of a bromodomain inhibitor compound (Compound A) having the following structure, or a pharma- ceutical acceptable salt thereof: [ka]

[0006] Aspects and embodiments of the present invention provide methods and pharmaceutical compositions for the treatment of subjects with prostate cancer, such as castration-resistant prostate cancer (CPRC), neuroendocrine prostate cancer (NEPC) and antiandrogen-resistant prostate cancer.

[0007] In one embodiment, provided is a method of treating prostate cancer in a subject in need thereof, comprising administering to a subject of the structure [ka] or a pharma- ceutical acceptable salt thereof; wherein the prostate cancer is castration-resistant prostate cancer (CPRC), neuroendocrine prostate cancer (NEPC), antiandrogen-resistant prostate cancer, or any combination thereof.

[0008] In some embodiments, prostate cancer is metastasis. In some embodiments, prostate cancer to be treated is in advanced stage. In some embodiments, prostate cancer to be treated is metastasis to other areas of the subject's body than the prostate. In some embodiments, prostate cancer to be treated recurs in the subject after a significant period of remission. In some embodiments, prostate cancer is castration-resistant prostate cancer (CPRC). In some embodiments, castration-resistant prostate cancer (CPRC) is an AR-independent disease characterized by a neuroendocrine phenotype with low or no androgen receptor (AR) expression. In some embodiments, prostate cancer is neuroendocrine prostate cancer (NEPC).

[0009] In some embodiments, the method substantially induces the cell cycle arrest of prostate cancer.In some embodiments, "substantially" is defined as at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 100% cell cycle arrest of prostate cancer.In some embodiments, the method completely induces the cell cycle arrest of prostate cancer.

[0010] In some embodiments, the method induces apoptosis of androgen-independent cancer cells.In some embodiments, the method results in the induction of apoptosis of about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more or about 100% of androgen-independent cancer cells.

[0011] In certain embodiments, (a) the method results in at least about a 70% reduction in cancer cell proliferation; (b) the method results in about a 70% to about a 99% reduction in cancer cell proliferation; (c) the method results in at least about an 80% reduction in cancer cell proliferation; (d) the method results in about an 80% to about a 99% reduction in cancer cell proliferation; and / or (e) the method results in about a 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% reduction in cancer cell proliferation.

[0012] In certain embodiments, (a) the methods result in at least about a 40% reduction in tumor size; (b) the methods result in between about a 40% and about a 99% reduction in tumor size; and / or (c) the methods result in about a 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% reduction in tumor size.

[0013] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is suitable for oral administration. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is in the form of a tablet, pill, sachet, or hard or soft gelatin capsule.

[0014] Both the foregoing summary and the following description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the invention, but should not be construed as limiting. Other objects, advantages and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention. [Brief description of the drawings]

[0015] [Figure 1] Illustrated are VCaP cells treated for 3 days with the indicated concentrations of Compound A. Proliferation was measured on day 0 and day 3 of treatment and percent proliferation was determined using a luciferase assay.

[0016] [Diagram 2]1 shows VCaP cells treated for 48 h with the indicated concentrations of Compound A. KLK3, TMPRSS2, MYC and HEXIM1 gene expression was determined by qPCR.

[0017] [Diagram 3] 1 shows LNCaP cells treated for 3 days with the indicated concentrations of Compound A. Proliferation was measured on day 0 and day 3 of treatment and percent proliferation was determined using a luciferase assay.

[0018] [Figure 4] 1 shows LNCaP cells treated for 48 hours with the indicated concentrations of Compound A. KLK3, MYC and HEXIM1 gene expression was determined by qPCR.

[0019] [Diagram 5] 2-2Rv1 cells treated for 3 days with the indicated concentrations of Compound A. Proliferation was measured on day 0 and day 3 of treatment and percent proliferation was determined using a luciferase assay.

[0020] [Figure 6] 22Rv1 cells treated for 48 hours with the indicated concentrations of Compound A. KLK3, TMPRSS2, MYC and HEXIM1 gene expression was determined by qPCR.

[0021] [Figure 7] DU145 cells were treated for 3 days with the indicated concentrations of Compound A. Proliferation was measured on day 0 and day 3 of treatment and percent proliferation was determined using a luciferase assay.

[0022] [Figure 8] 1 shows PC3 cells treated for 3 days with the indicated concentrations of Compound A. Proliferation was measured on day 0 and day 3 of treatment and percent proliferation was determined using a luciferase assay. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Detailed Description I. overview The present invention relates to a method of treating prostate cancer with a therapeutically effective amount of a bromodomain inhibitor having the structure of formula (I) or a pharma- ceutically acceptable salt thereof, in particular, the prostate cancer is castration-resistant prostate cancer (CPRC), neuroendocrine prostate cancer (NEPC), antiandrogen-resistant prostate cancer, or any combination thereof.

[0024] In any of the embodiments described herein, the present disclosure recognizes that the bromodomain inhibitor is present in an amount that substantially and / or completely induces cell cycle arrest of prostate cancer cells and induces cell death of prostate carcinoma and neuroendocrine prostate cancer cells.The present disclosure also encompasses methods in which prostate cancer metastasis is prevented and / or delayed.In other embodiments, the present disclosure also encompasses methods in which prostate cancer cell growth arrest is observed after short-term administration, for example, less than about 1 month.In other embodiments, prostate cancer cell growth arrest is observed in less than about 20 days, less than about 15 days, less than about 14 days, less than about 13 days, less than about 12 days, less than about 11 days, less than about 10 days, less than about 9 days, less than about 8 days, less than about 7 days, less than about 6 days, less than about 5 days, less than about 4 days, or less than about 3 days. The percentage of prostate cancer cell proliferation arrest observed after any of these time periods can be, for example, about 100%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25% or about 20%.

[0025] In particular, Example 1 details the ability of bromo and exodomain inhibitor (BETi) Compound A, which is 2-[3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol, to completely arrest cell proliferation and induce cell death in prostate carcinoma and neuroendocrine prostate cancer cells. Experiments utilized multiple clinically accepted cell models, including: (i) VCaP cells, which display features of clinical prostate carcinoma including prostate-specific antigen (PSA) and androgen receptor (AR) expression; (ii) LNCaP cells, established from a metastatic lesion of a human prostate adenocarcinoma; (iii) 22Rv1 cells, which express the AR splice variant AR-V7 that mediates resistance to AR antagonists such as enzalutamide, (iv) DU145 cells, and (v) PC3 cells, both of which are widely accepted NEPC cell models.

[0026] Specifically, VCaP cells, which display clinical prostate carcinoma characteristics including expression of PSA and AR, are used as a model to study prostate cancer progression and metastasis. To test the role of BET inhibition in prostate cancer, VCaP cells were treated with BETi compound A. As illustrated in Figure 1, which is a graph showing the percentage of VCaP cell proliferation (Y-axis) versus the amount of compound A (X-axis) at day 0 and DMSO, compound A provided complete (100%) growth arrest of VCaP proliferation at 0.1 μM compound A. Furthermore, compound A showed cytotoxic effects at the highest concentration (Figure 1).

[0027] Furthermore, BET proteins control AR signaling through the regulation of AR target genes. To test whether BETi regulates AR target genes, VCaP cells were treated with compound A and gene expression was measured. Two AR target genes, kallikrein-related peptidase 3 (KLK3) and transmembrane serine protease 2 (TMPRSS2), were both downregulated after treatment with compound A. A 96.9% downregulation of KLK3 was observed when cells were treated with 4 nM compound A compared to DMSO, while a 99.4% downregulation of KLK3 compared to DMSO was measured in cells treated with 40 nM compound A (Figure 2, top). A decrease in expression was also observed for TMPRSS2, with a 32.8% and 51.9% downregulation when cells were dosed with 4 nM or 40 nM compound A, respectively (Figure 2, top). BET target genes such as MYC and hexamethylene bis-acetamide-inducible protein 1 (HEXIM1) were also regulated by compound A. In cells treated with 4 nM compound A, a 91.4% decrease in MYC expression was observed, whereas a 95.7% MYC downregulation was measured in cells treated with 40 nM compound A. HEXIM1 was upregulated by 968.0% and 1257.5% compared to DMSO when 4 nM or 40 nM compound A was administered to VCaP cells (Figure 2, bottom).

[0028] Additionally, to further corroborate the role of BETi in prostate cancer, LNCaP cells were treated with the BETi Compound A. Treatment with Compound A provided complete (100%) growth arrest after only 3 days of treatment (Figure 3). Figure 3 is a graph showing percent LNCaP cell proliferation (Y-axis) versus amount of Compound A (X-axis) relative to day 0 and DMSO. These results showed a 100% reduction in cell proliferation in both VCaP and LNCaP cells.

[0029] Furthermore, AR signaling was monitored in LNCaP cells after treatment with compound A, and downregulation of KLK3 was observed, with 58.8% and 92.0% downregulation when cells were administered 4 nM or 40 nM, respectively (Figure 4). BETi target genes were also modulated. Downregulation of MYC of 84.1% was observed when cells were administered 4 nM compound A, and downregulation of 93.6% was measured when LNCaP cells were administered 40 nM compound A. Finally, upregulation of HEXIM1 of 446.8% and 533.3% was measured when cells were treated with compound A at 4 nM and 40 nM, respectively (Figure 4).

[0030] The current standard of care for prostate cancer involves androgen deprivation therapy (ADT), but after rapid remission, cancer cells eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). 22Rv.1 prostate cancer cells express the AR splice variant AR-V7, which mediates resistance to AR antagonists such as enzalutamide. This cell line was used as a model for CRPC. To test the role of BETi in CRPC, 22Rv.1 cells were treated with compound A. BETi negatively affected 22Rv.1 proliferation and increased IC 50 =0.0017 (Figure 5). Figure 5 is a graph showing percent 22RV.1 cell proliferation (Y-axis) versus amount of Compound A (X-axis) for day 0 and DMSO.

[0031] To determine the effect of Compound A on AR target genes, 22Rv.1 cells were treated with two different concentrations of Compound A (4 nM and 40 nM). Both AR target genes were strongly downregulated, with 99.9% or 99.8% downregulation observed for KLK3 when cells were administered 4 nM or 40 nM Compound A. A 97.0% or 97.8% reduction relative to DMSO was measured for TMPRSS2 when cells were treated with 4 nM or 40 nM Compound A, respectively (Figure 6, top). The BET target gene MYC was downregulated, with 98.5% downregulation when 4 nM Compound A was added and 99.3% downregulation when cells were treated with 40 nM Compound A. A 31% induction of HEXIM1 was observed when cells were treated with 4 nM Compound A, while a 91.5% upregulation was observed when cells were treated with 40 nM Compound A (Figure 6, bottom). Similar to what was observed in VCaP and LNCaP, CRPC 22Rv.1 cell proliferation was impaired and AR signaling was misregulated in BETi-treated cells.

[0032] Some CRPC patients develop AR-independent disease, characterized by a neuroendocrine (NE) phenotype with low or no AR expression. The mechanisms that lead to drug resistance and the development of the NE phenotype are not yet fully understood. Prostate cancer cells DU145 are an AR-negative cell line that does not respond to androgens. To test the effect of BETi in AR-negative cells, DU145 were treated with compound A, and a 61.9% reduction in DU145 proliferation was observed (Figure 7). Figure 7 is a graph illustrating the percentage of cell proliferation (Y-axis) of DU145 cells relative to day 0 and DMSO versus the amount of compound A (X-axis).

[0033] Prostate cancer cells PC3 are a widely accepted NEPC cell model. To further corroborate the effect of BETi on NEPC, PC3 cells were treated with Compound A. Compound A showed a 67% reduction in PC3 proliferation (IC 50 Compound A=0.0041) (FIG. 8). FIG. 8 is a graph illustrating percent cell proliferation (Y-axis) versus amount of Compound A (X-axis) for PC3 cells on day 0 and DMSO.

[0034] These data show that BETi Compound A caused a >61.9% decrease in cell proliferation in all neuroendocrine prostate cancer models tested.

[0035] Taken together, the data demonstrate the ability of BETi compound A to substantially and / or completely arrest cell proliferation and induce cell death in prostate carcinoma cells, supporting the use of compound A and structurally related compounds as novel targeted therapies for solid tumors.

[0036] Tricyclic compounds useful as bromodomain inhibitors are disclosed in US patent application Ser. No. 14 / 580,355 (US Pat. No. 9,458,155).

[0037] In any of the embodiments described herein, compound A has the structure: [ka] or a pharma- ceutical acceptable salt thereof. The chemical formula of the compound is C 30 H 33 N 5 O 2 and has a molecular weight of 495.62. The synthesis of this compound is disclosed in U.S. patent application Ser. No. 14 / 580,355 (U.S. Patent No. 9,458,155).

[0038] Pharmaceutically acceptable salts include salts of a compound formed by the reaction of the compound with a pharma- ceutically acceptable inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or with an acid such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanes ... The acid addition salts formed by the reaction of the compounds with pharma- ceutically acceptable inorganic acids include, but are not limited to, acid addition salts formed by the reaction of the compounds with organic acids such as, for example, acid addition salts formed by the reaction of the compounds with pharma- ceutically acceptable inorganic acids, such as, for example, acid addition salts formed by the reaction of the compounds with organic acids such as, for example, sulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like.

[0039] II. Pharmaceutical Compositions In any of the embodiments described herein, the bromodomain inhibitors described herein, or pharma- ceutically acceptable salts thereof, are formulated into a pharmaceutical composition.

[0040] Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations.Appropriate formulations depend on the route of administration selected.In some embodiments, the pharmaceutical compositions disclosed herein include one or more pharma- ceutically acceptable carriers, such as aqueous carriers, buffers and / or diluents.

[0041] Administration of the compounds and compositions described herein can be performed by any method that allows delivery of the compound to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories and rectal enemas), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intraspinal, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and topical (epicutaneous, transdermal, enema, eye drops, ear drops, intranasal) administration, most suitable routes will depend, for example, on the condition and disorder of the recipient. By way of example, the compounds described herein can be administered locally to the area requiring treatment, for example, by local infusion during surgery, topical application such as creams or ointments, injection, catheter or implant. Administration can also be direct injection into the site of the affected tissue or organ.

[0042] In some embodiments, pharmaceutical compositions suitable for oral administration are provided as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is provided as a bolus, electuary, or paste.

[0043] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be made by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, an inert diluent, or a lubricant, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the pulverized compound presented with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, a stabilizer. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Suitable non-toxic solid carriers also include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.

[0044] The compounds described herein may also be administered in combination or in coordination with a suitable carrier or vehicle depending on the route of administration. As used herein, the term "carrier" includes pharma- ceutically acceptable solid or liquid fillers, diluents, or encapsulants. Aqueous liquid carriers may contain pharma- ceutically acceptable additives, such as acidifiers, alkalinizers, antimicrobial preservatives, antioxidants, buffers, chelating agents, complexing agents, solubilizers, wetting agents, solvents, suspending and / or thickening agents, isotonicity agents, wetting agents, or other biocompatible substances. Lists of ingredients listed by the above categories can be found in the US Pharmacopeia National Formulary, 1857-1859, and (1990). Some examples of substances which may serve as pharma- ceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; additives 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; glycols such as propylene glycol; polyols such as glycerin, 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; isotonic saline; Ringer's solution, ethyl alcohol and phosphate buffer solutions and other non-toxic compatible substances used in pharmaceutical preparations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition as desired by the formulator.Examples of pharma- ceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0045] The pharmaceutical compositions of the present invention may also include one or more binders, fillers, lubricants, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other additives. Such additives are known in the art. Examples of fillers include lactose monohydrate, lactose anhydrous, and various starches; examples of binders include various celluloses and cross-linked polyvinylpyrrolidone, Avicel. (登録商標) PH101 and Avicel (登録商標) Microcrystalline Cellulose such as PH102, Microcrystalline Cellulose and Silicified Microcrystalline Cellulose (ProSolv SMCC TM Suitable lubricants include agents that affect the flowability of the powder as it is compressed, such as Aerosil (登録商標) Examples of sweeteners include colloidal silicon dioxide such as 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel. Examples of sweeteners include any natural or artificial sweetener such as sucrose, xylitol, sodium saccharin, cyclamic acid, aspartame, and acesulfame. Examples of flavoring agents include Magnasweet (登録商標) (trademark of MAFCO), bubble gum flavors and fruit flavors, etc. Examples of preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol or quaternary compounds such as benzalkonium chloride.

[0046] The pharmaceuticals used for therapeutic administration can be sterile. For example, they can be easily sterilized by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Any pharma- ceutically acceptable sterilization method can be used for the compositions of the present invention.

[0047] Pharmaceutical compositions containing the compounds described herein or salts thereof will be formulated and administered in a manner consistent with good medical practice, taking into account the clinical condition of the individual patient, the method of administration, the administration schedule, and other factors known to the practitioner.

[0048] III. Treatment The present application provides methods of treating prostate cancer using any of the bromodomain inhibitors described herein, or pharma- ceutically acceptable salts thereof.

[0049] In any of the embodiments described herein, a therapeutically effective amount of a bromodomain inhibitor can be used.In some embodiments, the therapeutically effective amount of a bromodomain inhibitor or its pharmaceutically acceptable salt is an amount that substantially induces cell cycle arrest of prostate cancer cells.In some embodiments, the therapeutically effective amount of a bromodomain 1 inhibitor or its pharmaceutically acceptable salt is an amount that completely induces cell cycle arrest of prostate cancer cells.In some embodiments, the therapeutically effective amount of a bromodomain inhibitor or its pharmaceutically acceptable salt is an amount that induces apoptosis of androgen-independent cancer cells.

[0050] In some embodiments of the methods described herein, the methods result in substantial induction of cell cycle arrest of prostate cancer cells, where "substantial" is defined as at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% cell cycle arrest of prostate cancer cells. Percent cell cycle arrest of prostate cancer cells can be measured using any clinically accepted technique.

[0051] In other embodiments of the methods described herein, the method results in complete induction of cell cycle arrest of prostate cancer cells. Cell cycle arrest of prostate cancer cells can be measured using any clinically accepted technique.

[0052] Finally, in other embodiments of the methods described herein, the methods result in the induction of apoptosis of androgen-independent cancer cells.For example, the methods can result in the induction of apoptosis of about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100% of androgen-independent cancer cells.The apoptosis of androgen-independent cancer cells can be measured using any clinically accepted technique.

[0053] In one aspect, provided is a method of treating prostate cancer in a subject in need of treatment comprising administering to the subject a composition comprising a bromodomain inhibitor or a pharma- ceutically acceptable salt thereof.

[0054] In any of the embodiments described herein, prostate cancer can be castration-resistant prostate cancer (CPRC), neuroendocrine prostate cancer (NEPC), antiandrogen-resistant prostate cancer, or any combination thereof.In some embodiments, prostate cancer is castration-resistant prostate cancer (CPRC).In some embodiments, prostate cancer is neuroendocrine prostate cancer (NEPC).In some embodiments, prostate cancer is antiandrogen-resistant prostate cancer.

[0055] In any of the embodiments described herein, the prostate cancer to be treated may be in an advanced stage. In any of the embodiments described herein, the prostate cancer may be metastatic. In any of the embodiments described herein, the prostate cancer to be treated may be metastatic to areas of the patient's body other than the prostate. In any of the embodiments described herein, the prostate cancer to be treated may have recurred in the patient after a significant period of remission.

[0056] In any of the embodiments described herein, the method may result in (a) at least about a 40% reduction in cancer cell proliferation; (b) about a 40% to about a 99% reduction in cancer cell proliferation; and / or (c) about a 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% reduction in cancer cell proliferation. In some embodiments, the method results in at least about a 40% reduction in cancer cell proliferation. In some embodiments, the method results in about a 40% to about a 99% reduction in cancer cell proliferation. In certain embodiments, the methods result in about a 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% reduction in cancer cell proliferation.

[0057] In any of the embodiments described herein, the method may result in (a) at least about a 40% reduction in tumor size; (b) about a 40% to about a 99% reduction in tumor size; and / or (c) about a 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% reduction in tumor size. In some embodiments, the method results in at least about a 40% reduction in tumor size. In some embodiments, the method results in about a 40% to about a 99% reduction in tumor size. In certain embodiments, the methods result in about a 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% reduction in tumor size.

[0058] A. Route of Administration Administration may be via any route of administration, non-limiting examples include nasal, sublingual, buccal, rectal, intravenous, intraarterial, intradermal, intraperitoneal, intrathecal, intramuscular, epidural, intracerebral, intraventricular, transdermal, or any combination thereof.

[0059] The compounds or pharmaceutical compositions described herein are administered in a manner appropriate for the disease to be treated and / or prevented. The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient and the method of administration. In general, an appropriate dose and treatment regimen provides a sufficient amount of the composition to provide a therapeutic and / or preventive benefit (e.g., improved clinical outcomes such as more frequent complete or partial remissions or long-term disease-free and / or overall survival or reduced severity of symptoms). Optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses depend on the patient's size, weight or blood volume.

[0060] In any of the embodiments described herein, the bromodomain inhibitor or a pharma- ceutically acceptable salt thereof is suitable for oral administration. Suitable forms for oral administration include, but are not limited to, tablets, pills, sachets, or hard or soft gelatin capsules.

[0061] B. Kit The compounds or compositions of the present invention described herein may be packaged or kitted with instructions or inserts. Such instructions or inserts may address the recommended storage conditions, such as time, temperature and light, that allow for the shelf life of the bromodomain inhibitor or its salt. Such instructions or inserts may also address the specific advantages of the compounds or derivatives or their salts described herein, such as ease of storage for formulations that may need to be used in the field, outside of controlled hospital, clinic or office conditions.

[0062] The present invention also provides pharmaceutical packs or kits comprising one or more containers filled with one or more of the pharmaceutical compositions disclosed herein. The kits may include containers filled with an appropriate amount of the pharmaceutical composition, for example, as a powder to be dissolved, a tablet, or as a sterile solution. Associated with such containers may be a notice in the form prescribed by a governmental authority regulating the manufacture, use, or sale of pharmaceutical or biological products, reflecting the agency's approval of the manufacture, use, or sale for human administration. Additionally, the bromodomain inhibitors or salts thereof may be used with other therapeutic compounds.

[0063] In some embodiments, the kit may include one or more devices, where the device may be packaged in a first protective package, a second protective package, or a third protective package that protects the physical integrity of the product. One or more of the first, second, or third protective packages may include a foil pouch. The kit may further include instructions for the use of the device. In some embodiments, the kit includes two or more devices.

[0064] In some embodiments, the kit may include the device and may further include instructions for use. In some embodiments, the instructions may include visual aids / images and / or instructions for the administrator of the device.

[0065] IV. definition The following definitions are provided to facilitate understanding of certain terms used throughout this specification.

[0066] Technical and scientific terms used herein may have the meaning commonly understood by those of ordinary skill in the art unless otherwise specified. Any suitable materials and / or methods known to those of ordinary skill in the art may be used in the practice of the methods described herein.

[0067] In this specification and the appended claims, unless the context clearly indicates otherwise, the singular terms "a," "an," and "the" are used interchangeably and are intended to include the plural forms as well as fall within the scope of each. Also, as used herein, "and / or" refers to one or more of the listed items and includes any and all possible combinations as well as non-combinations when interpreted as alternatives ("or").

[0068] As used herein, "about" is understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If the use of the term is not clear to persons of ordinary skill in the art from the context in which it is used, "about" will mean up to plus or minus 10% of the particular term.

[0069] As used herein, the term "administering" includes formulations for administration as well as the actual administration, including physical administration by the subject being treated or by another person.

[0070] As used herein, "subject," "patient," or "individual" refers to any subject, patient, or individual, and these terms are used interchangeably herein. In this context, the terms "subject," "patient," and "individual" include mammals, particularly humans. When used in conjunction with "in need of treatment," the term "subject," "patient," or "individual" contemplates any subject, patient, or individual having or at risk for a particular condition or disorder.

[0071] The term "therapeutically effective" or "effective" as used herein in the context of "dosage" or "amount" refers to a dose or amount that provides a specific pharmacological effect in a subject to which one or more compounds are administered. It is emphasized that a therapeutically effective amount is not always effective to achieve the intended effect in a subject, even if the dose is considered to be a therapeutically effective amount by those skilled in the art. For convenience only, exemplary dosage amounts are provided herein. Those skilled in the art can adjust such amounts according to the methods disclosed herein for the treatment of a particular subject with a particular condition or disorder. A therapeutically effective amount can vary based on the route of administration and dosage form.

[0072] The terms "treatment", "treat" or any variation thereof include the reduction, amelioration or elimination of (i) one or more specific symptoms and / or (ii) one or more symptoms or effects of a particular disorder. The terms "prevention", "prevent" or any variation thereof include the reduction, amelioration or elimination of the risk of occurrence of (i) one or more specific symptoms and / or (ii) one or more symptoms or effects of a particular disorder.

[0073] "Pharmaceutically acceptable salts" include both acid and base addition salts. A pharmaceutically acceptable salt of any of the substituted heterocyclic derivative compounds described herein is intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0074] "Pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphoric acid, etc. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, example salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitro-benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate, gluconate and galacturonate (see, e.g., Berge SM et al., Pharmaceutical Salts, J. Pharma. Sci. 66:1-19 (1997)). Acid addition salts of basic compounds are prepared, in certain embodiments, by contacting the free base form with a sufficient amount of the desired acid following methods and techniques familiar to those skilled in the art for forming salts.

[0075] "Pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid, without being biologically or otherwise undesirable. These salts are formed by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra. EXAMPLES

[0076] As used in the following examples, Compound A refers to 2-[3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol.

[0077] The list below identifies the abbreviations used in the following examples. [Table 1]

[0078] Example 1 The following example evaluates the ability of BETi Compound A to completely arrest cell growth and induce cell death in prostate carcinoma and neuroendocrine prostate cancer cells.

[0079] material and method cell culture VCaP, LNCaP, 22Rv.1, DU145 and PC3 cancer cell lines were obtained from ATCC. VCaP was cultured in DMEM medium supplemented with 8% FBS, LNCaP, 22Rv.1 and DU145 in RPMI1640 medium supplemented with 10% FBS, and PC3 in F12K medium supplemented with 10% FBS.

[0080] Proliferation assay Cells were seeded in a 96-well format and allowed to attach for 24 hours prior to treatment. Drugs were titrated 1:3 from 1 μM to 0.1 nM for 9 doses in triplicate. Cell proliferation was measured on the day of treatment (day 0) and day 3 using Cell Titer-Glo reagent (Promega) according to the manufacturer's instructions. Cell proliferation normalized to DMSO media control and day 0 was fitted by nonlinear regression using GraphPad Prism 7.03 (GraphPad Software, Inc.).

[0081] Gene expression analysis Cells were seeded in a 6-well format and allowed to attach for 24 hours before treatment. Cells were treated for 48 hours and then collected. RNA was purified from cells using the RNeasy kit (Qiagen) according to the manufacturer's instructions. Quantitative RTPCR was performed using the TaqMan assay (Thermo Fisher Scientific) on an ABI QuantStudio 7 Flex Real-Time PCR System.

[0082] result Compound A brings about a complete growth arrest and induces cell death of prostate carcinoma cells. VCaP cells exhibit clinical prostate carcinoma characteristics, including expression of prostate-specific antigen (PSA) and androgen receptor (AR), and are used as a model to study prostate cancer progression and metastasis. To test the role of BET inhibition in prostate cancer, VCaP cells are treated with the BET inhibitor (BETi) compound A. Compound A affects VCaP proliferation at 0.1 μM, causing complete (100%) growth arrest. Moreover, at the highest concentration compound A exhibits cytotoxic effects (Figure 1). BET proteins control AR signaling through the regulation of AR target genes. To test whether BETi regulates AR target genes, VCaP cells were treated with compound A and gene expression was measured. Two AR target genes, kallikrein-related peptidase 3 (KLK3) and transmembrane serine protease 2 (TMPRSS2), are both downregulated after treatment with compound A. A 96.9% downregulation of KLK3 was observed when cells were treated with 4 nM compound A, while a 99.4% downregulation was observed when cells were treated with 40 nM compound A (Figure 2, top). Downregulation was also observed for TMPRSS2, with 32.8% and 51.9% downregulation when cells were dosed with 4 nM or 40 nM compound A, respectively (Figure 2, top). BET target genes, such as MYC and hexamethylene bis-acetamide-induced protein 1 (HEXIM1), were also regulated by compound A. A 91.4% reduction in MYC expression was observed in cells treated with 4 nM compound A, whereas a 95.7% MYC downregulation was measured in cells treated with 40 nM compound A. HEXIM1 was upregulated by 968.0% and 1257.5% compared to DMSO when 4 nM or 40 nM compound A was administered to VCaP cells (Figure 2, bottom). To further corroborate the role of BETi in prostate cancer, LNCaP cells, established from metastatic lesions of human prostate adenocarcinoma, were treated with Compound A. Treatment with Compound A caused complete (100%) growth arrest at 1 μM (Figure 3). AR signaling was monitored in LNCaP cells after treatment with compound A, and downregulation of KLK3 was observed, with 58.8% and 92.0% downregulation when cells were administered 4 nM or 40 nM, respectively (Figure 4). BETi target genes were also modulated. Downregulation of MYC of 84.1% was observed when cells were administered 4 nM compound A, and downregulation of 93.6% was measured when LNCaP cells were administered 40 nM compound A. Finally, upregulation of HEXIM1 of 446.8% and 533.3% was measured when cells were treated with compound A at 4 nM and 40 nM, respectively (Figure 4).

[0083] Compound A impairs the proliferation of castration-resistant prostate cancer cells. The current standard of care for prostate cancer consists of androgen deprivation therapy (ADT), but after rapid remission, cancer cells eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). 22Rv.1 prostate cancer cells express the AR splice variant AR-V7, which mediates resistance to AR antagonists such as enzalutamide. This cell line was used as a model for CRPC. To test the role of BETi in CRPC, 22Rv.1 cells were treated with compound A. BETi negatively affected 22Rv.1 proliferation and increased IC 50 =0.0017 (Figure 5). To determine the effect of Compound A on AR target genes, 22Rv.1 cells were treated with two different concentrations of Compound A (4 nM and 40 nM). Both AR target genes were strongly downregulated, with 99.9% or 99.8% downregulation observed for KLK3 when cells were treated with 4 nM or 40 nM Compound A. A 97.0% or 97.8% reduction relative to DMSO was measured for TMPRSS2 when cells were treated with 4 nM or 40 nM Compound A, respectively (Figure 6, top). The BET target gene MYC was downregulated, with 98.5% downregulation when 4 nM Compound A was added and 99.3% downregulation when cells were treated with 40 nM Compound A. HEXIM1 was upregulated, with 31% induction observed when cells were treated with 4 nM compound A, whereas 91.5% upregulation was observed when cells were treated with 40 nM compound A (Figure 6, bottom). Similar to what was observed in VCaP and LNCaP, CRPC 22Rv.1 cell proliferation was impaired and AR signaling was misregulated in BETi-treated cells.

[0084] Compound A potently reduces the proliferation of neuroendocrine prostate cancer cells. A proportion of CRPC patients develop AR-independent disease, characterized by a neuroendocrine (NE) phenotype with low or absent AR expression. Prostate cancer cell DU145 is an AR-negative cell line that does not respond to androgens. To test the effect of BETi in AR-negative cells, DU145 was treated with compound A, and a 61.9% decrease in DU145 proliferation was observed (Figure 7). Prostate cancer cell PC3 is another AR-negative cell line that is widely accepted as a NEPC cell model. To test the effect of BETi on NEPC, PC3 cells were treated with compound A. Compound A showed a 67% reduction in PC3 proliferation, with an IC 50 =0.0041 (Figure 8).

[0085] Taken together, our data demonstrate the ability of compound A to arrest cell proliferation and affect AR signaling in prostate carcinoma cells, indicating its potential as a novel and targeted therapy for these solid tumors.

[0086] While certain embodiments have been illustrated and described, it is to be understood that modifications and adaptations can be made in accordance with ordinary skill in the art without departing from the broad scope of the technology defined in the following claims.

[0087] The embodiments illustratively described herein may suitably be practiced in the absence of any one or more elements or limitations not specifically disclosed herein. Thus, for example, the terms "comprise", "include", "contain", etc., should be interpreted broadly and without limitations. Furthermore, the terms and expressions used herein are used in a descriptive sense, and the use of such terms and expressions is not intended to exclude any equivalents of the properties shown and described, or portions thereof, but rather recognizes that various modifications are possible within the scope of the claimed technology. Furthermore, the term "consisting essentially of" is understood to include the elements specifically mentioned and additional elements that do not materially affect the basic and novel properties of the claimed technology. The term "consisting of" excludes any elements not specified.

[0088] The present disclosure should not be limited in terms of the specific embodiments described herein. As will be apparent to those skilled in the art, many modifications and variations can be made without departing from the spirit and scope of the present invention. In addition to those listed herein, functionally equivalent methods and compositions within the scope of the present invention will be apparent to those skilled in the art from the above. Such modifications and variations are intended to fall within the scope of the appended claims. The present invention is limited only in terms of the appended claims, along with the full scope of equivalent equivalents to which such claims are entitled. It should be understood that the present invention is not limited to specific methods, reagents, compounds or compositions, which may of course vary. It should also be understood that the terms used herein are used only for the purpose of describing specific embodiments, and are not intended to be limiting.

[0089] Further, when properties or aspects of the present invention are described in terms of a Markush group, one of skill in the art will recognize that the invention also is described in terms of any individual member or subgroup of members of that Markush group.

[0090] As will be understood by those skilled in the art, for any and all purposes, particularly in terms of providing written descriptions, all ranges disclosed herein also include any and all possible subranges and combinations of subranges, including the endpoints. It can be easily recognized that any recited range fully describes and allows the same range to be broken down into at least equal halves, 1 / 3, 1 / 4, 1 / 5, 1 / 10, etc. As a non-limiting example, each range described herein can be easily broken down into a lower 1 / 3, a middle 1 / 3, and an upper 1 / 3, etc. As will also be understood by those skilled in the art, terms such as "up to," "at least," "greater than," "less than," etc. refer to ranges that are inclusive of the recited numerical values ​​and can then be broken down into subranges as described above. Finally, as will be understood by those skilled in the art, ranges include individual members.

[0091] All publications, patent applications, issued patents, and other documents mentioned herein are incorporated by reference to the same extent as if each individual publication, patent application, issued patent, and other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the documents incorporated by reference are excluded to the extent that they conflict with definitions herein.

[0092] Other embodiments are set forth in the following claims.

Claims

1. Structure 【Chemistry 1】 A pharmaceutical composition for treating prostate cancer, comprising compound A represented by the formula: or a pharma- ceutically acceptable salt thereof, wherein the prostate cancer is castration-resistant prostate cancer (CPRC), neuroendocrine prostate cancer (NEPC), antiandrogen-resistant prostate cancer, or any combination thereof.

2. The pharmaceutical composition of claim 1 , wherein the prostate cancer is metastatic.

3. The pharmaceutical composition of claim 1, wherein the prostate cancer to be treated is at an advanced stage.

4. 10. The method of claim 1, wherein the prostate cancer to be treated has metastasized to areas of the subject's body other than the prostate.

5. 10. The method of claim 1, wherein the prostate cancer being treated has recurred in the subject after a significant period of remission.

6. 2. The pharmaceutical composition of claim 1, wherein the prostate cancer is castration-resistant prostate cancer (CPRC).

7. The pharmaceutical composition according to claim 6, wherein castration-resistant prostate cancer (CPRC) is an androgen receptor (AR)-independent disease characterized by a neuroendocrine phenotype with low or absent AR expression.

8. The pharmaceutical composition of claim 1, wherein the prostate cancer is neuroendocrine prostate cancer (NEPC).

9. The pharmaceutical composition of claim 1, which substantially induces cell cycle arrest in prostate cancer.

10. The pharmaceutical composition of claim 9, wherein "substantial" is defined as at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 100% cell cycle arrest of the prostate cancer.

11. The pharmaceutical composition of claim 1, which completely induces cell cycle arrest in prostate cancer.

12. The pharmaceutical composition described in claim 1, which induces apoptosis of androgen-independent cancer cells.

13. The pharmaceutical composition of claim 12, which induces apoptosis in about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more or about 100% of androgen-independent cancer cells.

14. (a) resulting in at least about a 70% reduction in cancer cell proliferation; (b) resulting in about a 70% to about 99% reduction in cancer cell proliferation; (c) resulting in at least about an 80% reduction in cancer cell proliferation; (d) causing about 80% to about 99% reduction in cancer cell proliferation; and / or (e) resulting in about a 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% reduction in cancer cell proliferation; The pharmaceutical composition of claim 1.

15. (a) resulting in at least about 40% reduction in tumor size; (b) causing about a 40% to about 99% reduction in tumor size; and / or (c) resulting in about a 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% reduction in tumor size. The pharmaceutical composition of claim 1.

16. A pharmaceutical composition according to claim 1 for oral administration.

17. The pharmaceutical composition of claim 16 in the form of a tablet, pill, sachet or hard or soft gelatin capsule.

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