Search

EP-4734996-A1 - COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ANDROGEN RECEPTOR

EP4734996A1EP 4734996 A1EP4734996 A1EP 4734996A1EP-4734996-A1

Abstract

This disclosure pertains to methods of treating prostate cancer in a subject in need thereof, including, for example, metastatic prostate cancer, castrate-resistant prostate cancer, and metastatic castrate-resistant prostate cancer, wherein the method comprises administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and further comprises a step of discontinuing or reducing the administration of a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor, to the subject prior to initiating administration of Compound A, or the pharmaceutically acceptable salt thereof.

Inventors

  • ZHANG, Jingang George
  • SNYDER, LAWRENCE B.
  • HUANG, YONGQING

Assignees

  • Arvinas Operations, Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (15)

  1. 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, or a pharmaceutically acceptable salt thereof, further comprising a step of discontinuing or reducing the administration of a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor, to the subject prior to initiating administration of Compound A, or the pharmaceutically acceptable salt thereof.
  2. 2. A method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound A, further comprising a step of discontinuing or reducing the administration of a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor to the subject prior to initiating administration of Compound A.
  3. 3. The method of claim 1 or 2, further comprising the step of discontinuing the administration of the CYP3A inhibitor or inducer, efflux transporter substrate or inhibitor, or uptake transporter substrate or inhibitor to the subject prior to initiating administration of Compound A, or the pharmaceutically acceptable salt thereof.
  4. 4. The method of claim 1 or 2, further comprising the step of reducing the administration of the CYP3A inhibitor or inducer, efflux transporter substrate or inhibitor, or uptake transporter substrate or inhibitor to the subject prior to initiating administration of a therapeutically effective amount of Compound A, or the pharmaceutically acceptable salt thereof.
  5. 5. The method of claim 3, wherein the administration of the CYP3A inhibitor or inducer, efflux transporter substrate or inhibitor, or uptake transporter substrate or inhibitor is discontinued in the subject beginning at a time point prior to initiating the administration of Compound A, or the pharmaceutically acceptable salt thereof, wherein the time point is at least 120 hours.
  6. 6. The method of claim 4, wherein the administration of the CYP3A inhibitor or inducer, efflux transporter substrate or inhibitor, or uptake transporter substrate or inhibitor is reduced in the subject at a time point prior to initiating the administration of Compound A, or the pharmaceutically acceptable salt thereof, wherein the time point is at least 120 hours.
  7. 7. A method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, further comprising a step of administering a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor to the subject.
  8. 8. A method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound A, further comprising a step of administering a CYP3A inhibitor or inducer, an efflux transporter substrate or inhibitor, or an uptake transporter substrate or inhibitor to the subject.
  9. 9. The method of any one of claims 1-8, wherein the prostate cancer is castrate-resistant prostate cancer.
  10. 10. The method of any one of claims 1-8, wherein the prostate cancer is metastatic prostate cancer.
  11. 11. The method of any one of claims 1-8, wherein the prostate cancer is metastatic castrateresistant prostate cancer.
  12. 12. The method of any one of claims 1-11, wherein the subject is in a fed state.
  13. 13. The method of any one of claims 1-11, wherein the subject is in a fasted state.
  14. 14. The method of any one of claims 1-13, wherein the efflux transporter is Pgp or BCRP.
  15. 15. The method of any one of claims 1-14, wherein the uptake transporter is 0ATP1B1, 0ATP1B3, 0AT1, 0AT3, OCT2, MATE1, or MATE2-K.

Description

COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ANDROGEN RECEPTOR RELATED APPLICATIONS [0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63/511,420, filed June 30, 2023, and U.S. Provisional Application No. 63/580,126, filed September 1, 2023, the contents of each of which are incorporated herein by reference in their entirety for all purposes. TECHNICAL FIELD [0002] The disclosure provides methods of using bifunctional compounds for treating prostate cancer. BACKGROUND OF THE DISCLOSURE [0003] Most small molecule drugs bind enzymes or receptors in tight and well-defined pockets. On the other hand, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination, and are therefore attractive therapeutic targets. The development of ligands of E3 ligases has proven challenging, in part due to the fact that they must disrupt proteinprotein interactions. However, recent developments have provided specific ligands which bind to these ligases. [0004] One E3 ubiquitin ligase with therapeutic potential is cereblon. Cereblon is a protein that in humans is encoded by the CRBN gene. Thalidomide and its analogs, e.g., pomalidomide and lenalidomide, are known to bind cereblon. These agents bind to cereblon, altering the specificity of the complex to induce the ubiquitination and degradation of transcription factors essential for multiple myeloma growth. Indeed, higher expression of cereblon has been linked to an increase in efficacy of imide drugs in the treatment of multiple myeloma. [0005] Androgen Receptor (AR) belongs to a nuclear hormone receptor family that is activated by androgens, such as testosterone and dihydrotestosterone (Pharmacol. Rev. 2006, 58(4), 782-97; Vitam. Horn. 1999, 55:309-52.). In the absence of androgens, AR is bound by Heat Shock Protein 90 (Hsp90) in the cytosol. When an androgen binds AR, its conformation changes to release AR from Hsp90 and to expose the Nuclear Localization Signal (NLS). The latter enables AR to translocate into the nucleus where AR acts as a transcription factor to promote gene expression responsible for male sexual characteristics (Endocr. Rev. 1987, 8(1): 1-28; Mol. Endocrinol. 2002, 16(10), 2181-7). AR deficiency leads to Androgen Insensitivity Syndrome, formerly termed testicular feminization. [0006] While AR is responsible for development of male sexual characteristics, it is also a well-documented oncogene in certain forms of cancers including prostate cancers (Endocr. Rev. 2004, 25(2), 276-308). A commonly measured target gene of AR activity is the secreted Prostate Specific Antigen (PSA) protein. The current treatment regimen for prostate cancer involves inhibiting the androgen-AR axis by two methods. The first approach relies on reduction of androgens, while the second strategy aims to inhibit AR function (Nat. Rev. Drug Discovery, 2013, 12, 823-824). Despite the development of effective targeted therapies, most patients develop resistance and the disease progresses. An alternative approach for the treatment of prostate cancer involves eliminating the AR protein. [0007] Because AR is a critical driver of tumorigenesis in many forms of prostate cancers, its elimination should lead to a therapeutically beneficial response. There exists an ongoing need in the art for effective treatments for diseases, especially cancer, prostate cancer, and Kennedy's Disease. [0008] However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents. As such, small molecule therapeutic agents that leverage or potentiate cereblon's substrate specificity and, at the same time, are "tunable" such that a wide range of protein classes can be targeted and modulated with specificity would be very useful as a therapeutic. [0009] Over 70 different somatic missense AR tumor mutation have been identified in patients with prostate cancer (Gottlieb, B., Hum. Mutat. 2004, 23: 527-533). The majority of these AR tumor mutations reside in the ligand binding domain. Without being bound by theory, AR tumor mutations in the ligand binding domain result in decreased ligand specificity, thereby enabling AR to function independently of androgen. Such AR tumor mutations provide tumor cells with the capability to proliferate in androgen-depleted environments, and thus are selected in response to therapies for prostate cancer that block or reduce androgen levels (e.g., luteinizing hormone- rel easing hormone agonists). Accordingly, AR tumor mutations are observed with increased frequency in patients having advanced, androgen-independent tumors as compared to patients having early-stage prostat