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Msg  10311 of 10562  at  9/22/2022 9:41:06 AM  by

JBWIN


Building IP: BMY Patent Appl. re "METHODS OF TREATING PROSTATE CANCER"

United States Patent Application20220296574
Kind CodeA1
Malatesta; Martina ; et al.September 22, 2022

METHODS OF TREATING PROSTATE CANCER

Abstract

The present application relates generally to methods for treating prostate cancer with substituted tricyclic derivative is 2-[3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methy- l]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol as a bromodomain inhibitor, or the pharmaceutically acceptable salt thereof.


Inventors:Malatesta; Martina; (San Francisco, CA) ; Filvaroff; Ellen Hope; (San Francisco, CA)
Applicant:
NameCityStateCountryType

Bristol-Myers Squibb Company

Princeton

NJ

US
Family ID:1000006430804
Appl. No.:17/653717
Filed:March 7, 2022

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
63160319Mar 12, 2021

Current U.S. Class:1/1
Current CPC Class:A61P 35/00 20180101; A61K 31/437 20130101
International Class:A61K 31/437 20060101 A61K031/437; A61P 35/00 20060101 A61P035/00

Claims



1. A method of treating prostate cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound A having the structure, ##STR00004## or a pharmaceutically acceptable salt thereof; and wherein the prostate cancer is castration resistant prostate cancer (CPRC), neuroendocrine prostate cancer (NEPC), anti-androgen resistant prostate cancer, or any combination thereof.

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

3. The method of claim 1, wherein the prostate cancer to be treated is in an advanced stage.

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

5. The method of claim 1, wherein the prostate cancer to be treated has re-occurred in the subject following a significant period of remission.

6. The method of claim 1, wherein the prostate cancer is castration resistant prostate cancer (CPRC).

7. The method of claim 6, wherein the castration resistant prostate cancer (CPRC) is an androgen receptor (AR) independent disease characterized by neuroendocrine phenotype with a low or absent AR expression.

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

9. The method of claim 1, wherein the method results in substantially inducing cell cycle arrest of the prostate cancer.

10. The method of claim 9, wherein "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 the prostate cancer.

11. The method of claim 1, wherein the method results in completely inducing cell cycle arrest of the prostate cancer.

12. The method of claim 1, wherein the method induces apoptosis of androgen independent cancer cells.

13. The method of claim 12, wherein the method results in inducing 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% apoptosis of the androgen independent cancer cells.

14. The method of claim 1, wherein: (a) the method results in at least about 70% reduction of cancer cell proliferation; (b) the method results in from about 70% to about 99% reduction of cancer cell proliferation; (c) the method results in at least about 80% reduction of cancer cell proliferation; (d) the method results in from about 80% to about 99% reduction of cancer cell proliferation; and/or (e) the method results in about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% reduction of cancer cell proliferation.

15. The method of claim 1, wherein: (a) the method results in at least about 40% reduction of tumor size; (b) the method results in from about 40% to about 99% reduction of tumor size; and/or (c) the method results in about 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 of tumor size.

16. The method of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, is adapted for oral administration.

17. The method of claim 16, wherein the compound, or a pharmaceutically acceptable salt thereof, is in the form of a tablet, pill, sachet, or capsule of hard of soft gelatin.
Description



CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is entitled to priority pursuant to 35 U.S.C. .sctn. 119(e) to U.S. provisional patent application No. 63/160,319, filed Mar. 12, 2021, which is incorporated herein in its entirety.

FIELD

[0002] The present application relates generally to compositions and methods for treating prostate cancer with a substituted heterocyclic derivative compound, or pharmaceutically acceptable salt thereof, as a bromodomain inhibitor.

BACKGROUND

[0003] Prostate cancer is the second leading cause of cancer-related death and the most commonly diagnosed cancer in men. Prostate cancer tumors are composed 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 are steroid receptors that function as transcription factors and control survival of the cells through mechanisms that remain unclear. Depletion of androgens causes death of normal prostate luminal epithelial cells, which demonstrates the critical role of the AR pathway in their survival. Cancerous prostate cells continue to express AR and their survival also depends on the presence of androgens, which makes androgen deprivation the therapy of choice for patients with advanced prostate cancers. First-line treatments for prostate cancer aim to reduce circulating androgen levels through the use of androgen deprivation therapies (ADT). While ADT is initially effective at reducing prostate cancer growth, after two to three years of treatment the majority of patients progress to castration-resistant prostate cancer (CRPC) and tumor growth will proceed even in the presence of castration levels of androgen. At this point of disease progression, the number of therapeutic options becomes very limited.

[0004] Thus, there remains a need for more effective treatments for prostate cancer, and this disclosure satisfies this need.

SUMMARY

[0005] The present application relates generally to compositions and methods for treating prostate cancer. The methods comprise administering a therapeutically effective amount of a bromodomain inhibitor compound (Compound A) having the structure, or a pharmaceutically acceptable salt thereof:

##STR00001##

[0006] The aspects and embodiments of the present disclosure provide for methods and pharmaceutical compositions for treating subjects with prostate cancer, such as castration resistant prostate cancer (CPRC), neuroendocrine prostate cancer (NEPC), and anti-androgen resistant prostate cancer.

[0007] Provided in one aspect is a method of treating prostate cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound A having the structure,

##STR00002##

or a pharmaceutically acceptable salt thereof; and wherein the prostate cancer is castration resistant prostate cancer (CPRC), neuroendocrine prostate cancer (NEPC), anti-androgen resistant prostate cancer, or any combination thereof.

[0008] In some embodiments, the prostate cancer is metastatic. In some embodiments, the prostate cancer to be treated is in an advanced stage. In some embodiments, the prostate cancer to be treated has metastasized to regions of the subject's body other than the prostate gland. In some embodiments, the prostate cancer to be treated has re-occurred in the subject following a significant period of remission. In some embodiments, the prostate cancer is castration resistant prostate cancer (CPRC). In some embodiments, the castration resistant prostate cancer (CPRC) is an androgen receptor (AR) independent disease characterized by neuroendocrine phenotype with a low or absent AR expression. In some embodiments, the prostate cancer is neuroendocrine prostate cancer (NEPC).

[0009] In some embodiments, the method results in substantially inducing cell cycle arrest of the 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 the prostate cancer. In some embodiments, the method results in completely inducing cell cycle arrest of the prostate cancer.

[0010] In some embodiments, the method induces apoptosis of androgen independent cancer cells. In some embodiments, the method results in inducing 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% apoptosis of the androgen independent cancer cells.

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

[0012] In some embodiments, (a) the method results in at least about 40% reduction of tumor size; (b) the method results in from about 40% to about 99% reduction of tumor size; and/or (c) the method results in about 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 of tumor size.

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

[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 are not to 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.


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