Modulation of Androgen Receptor for Therapeutic Application in Cancer and Viral Infection

Important Compound Classes

Title

Androgen Receptor Modulators and Methods for Their Use.

Patent Publication Number

WO 2020/081999 A1

Publication Date

April 23, 2020

Priority Application

US 62/747,209; US 62/803,516; US 62/857,516.

Priority Date

October 18, 2018; February 10, 2019; June 05, 2019.

Inventors

Zhou, H.; Virsik, P.

Assignee Company

ESSA Pharma, Inc. [CA/CA]; 999 West Broadway, Suite 720, Vancouver, British Columbia V5Z IK5, Canada.

Disease Area

Prostate Cancer

Biological Target

Androgen Receptor (AR).

Summary

Prostate cancer (PC) is the most common solid organ cancer and the second leading cause of cancer death for men in developed countries. Huggins and Hodges, over four decades ago first demonstrated the dependency of prostate cancer on androgen receptor activation for growth and survival. The risk factors in developing PC include family history, diet, race, age, and lifestyle. The development of prostate carcinogenesis has been demonstrated by androgens induced prostatic carcinogenesis in rodent models. In addition, men receiving androgens as anabolic steroids have shown higher incidence of prostate cancer. On the other hand, humans or dogs castrated before puberty show involution of the prostate and apoptosis of prostatic cells. The dependency on androgens provides the underlying therapeutic rationale for treating prostate cancer with chemical or surgical castration, also known as androgen depravation therapy (ADT) or androgen ablation therapy (ABT).

Elevated levels of androgens are associated with an increased risk of developing ovarian cancer in the majority of cases, whereas progesterone receptor and estrogen receptor-alpha are detected in less than 50% of ovarian tumors. The main therapeutic option of advanced PC is androgen deprivation therapy (ADT); however, clinical outcomes are limited. While common anticancer therapies can treat androgen-dependent PC, efficacy is limited for androgen-independent and castration-resistant prostate cancer (CRPC), which shows resistance to hormonal therapy. Thus, there is an urgent need for the identification of new therapeutic targets for the treatment of CRPC. Most cases of mCRPC are characterized by the restoration of the AR transcriptional activity and are evidenced by the rise in serum levels of prostate-specific antigen (PSA). Androgen ablation therapy causes a temporary reduction in tumor, which corrects to a decrease in serum prostate-specific antigen (PSA). However, PC can eventually grow again in the absence of testicular androgens, also known as castration-resistant disease, and most patients succumb to their disease within two years.

Androgens mediate their effects through the androgen receptor (AR), which plays a role in a wide range of developmental and physiological responses and in male sexual differentiation. AR is a member of the nuclear receptor (NR) superfamily. When AR binds to endogenous androgenic ligands such as testosterone and dihydrotestosterone (DHT), it localizes to the nucleus and binds the androgen response element in order to regulate the transcription of androgen sensitive genes. AR can also be activated in the absence of androgen by stimulation of the cAMP-dependent protein kinase pathway, with interleukin-6 and by various growth factors.

AR has distinct functional domains, which include the carboxy-terminal ligand-binding domain (LBD), a DNA-binding domain (DBD) comprising two zine finger motifs, and an N-terminus domain that contains two transcriptional activation units (taul and tau5) within activation function-1. AR inhibition either directly or indirectly targets the AR LBD; however, mutations in this domain in addition to constitutively active AR-splice variants that lack the LBD have been directly implicated in the clinic as being associated with both primary and acquired resistance. An alternative approach is to target the N-terminal domain (NTD) of the AR. The NTD contains key motifs responsible for interacting with coregulatory molecules that is essential for the transcriptional activity of the AR.

This Patent Highlight has representative compounds that can be useful for modulating AR, in order to treat various diseases and conditions including prostate cancer or breast cancer. In addition, pharmaceutically acceptable salt or solvate comprises one or more additional therapeutically active agents are useful in treating cardiovascular disease, neurological disease, a disorder characterized by abnormal accumulation of α-synuclein, a disorder of an aging process, bacterial infection, mental retardation, viral infection, mitochondrial related disease, deafness, blindness, diabetes, obesity, autoimmune disease, and rheumatoid arthritis.

Definitions

A and B are independently aryl or heteroaryl;

C = 3- to 10-membered ring;

X = -(CR⁵R⁶)-, -O-, -C(=O)-, -S-, -SO₂-, NSO₂R⁷-, and so forth;

Y and Z are independently -O-, -SO₂-, or -NR⁷;

W and V are independently -C(=O)-, -CONR⁷-, or -NSO₂R⁷-;

L = -CF₃, -CN, OR¹⁰, -NR¹¹R¹².

Key Structures

Biological Assay

Luciferase assay, ligand-binding domain (LBD)-expression reporter assay, cell proliferation assay, and AR-V7 transcriptional activity assay. In addition, microsomal and hepatocyte stability assays were carried out, alongside the in vivo pharmacokinetic properties (PK).

Biological Data

The table below shows IC₅₀ ranges of exemplary compounds in the androgen-induced PSA-luciferase assay, where *** represents IC₅₀ < 500 nM and ** represents IC₅₀ 500–2000 nM. PK parameters after single dose (5 mg/kg) in male CD-1 mice for compound A74 showed t_1/2 (h) = 12.5 and F (%) = 71.9.

Recent Review Articles

• 1.Luan H.; Xu P.; Meng Y.; Li Z.; Bian J.. Bioorg. Med. Chem. 2020, 28, 115554.
• 2.Anestis A.; Zoi I.; Papavassiliou A. G.; Karamouzis M. V.. Molecules 2020, 25, 358.
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• 4.Li D.; Zhou W.; Pang J.; Tang Q.; Zhong B.; Shen C.; Xiao L.; Hou T.. Med. Res. Rev. 2019, 39, 1485.
• 5.Nwachukwu F.; Foster O.. Eur. J. Biomed. Pharm. Sci. 2019, 6, 92.

The author declares no competing financial interest.