Therapeutic Strategies to Target the Androgen Receptor

Abstract

The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.

Discovery of ARD-2051 as a Potent and Orally Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer

“…DIPEA (5 equiv) was added to a solution of the compounds 61 and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione 56 (1.1 equiv) in DMSO (2 mL). After 4 h at 80 °C, the mixture was to HPLC purification to afford compounds 18−29 with 70−91% [4.5]decan-2-yl)benzonitrile (18). 1 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)benzoyl)-2,8diazaspiro [4.5]decan-2-yl)benzonitrile (20).…”

“…Because PROTAC degraders typically have MW greater than 700, achieving oral bioavailability has been a major challenge . However, through extensive medicinal chemistry efforts, a number of potent and orally active AR degraders have been reported, as represented by ARV-110, ARD-2128, and ARD-2585 (Figure ) using a cereblon ligand. − Importantly, several orally active AR degraders, including ARV-110, have been advanced into clinical development . Early clinical data showed that ARV-110 has a good safety profile and demonstrates clinical activity in patients heavily treated with second-generation AR antagonists or abiraterone, particularly for those patients carrying AR T878 and/or H875 mutations .…”

Targeted Degradation of Androgen Receptor for the Potential Treatment of Prostate Cancer

“…The table below show degradation of exemplary compounds in LNCaP and/or VCaP cells: A, <1 nM; B, 1–10 nM; C, 10–100 nM. …”

A Comprehensive Overview of Small-Molecule Androgen Receptor Degraders: Recent Progress and Future Perspectives

“…Collectively, targeting AR degradation has recently attracted considerable interest in the development of new anti-androgens for CRPC therapy, and great progress has been made, especially in the AR-targeted PROTACs as highlighted by several clinical candidates. Complementary to antagonizing AR function by novel strategies that has been introduced elsewhere, − strategies for reducing AR expression at the protein level will be systematically reviewed here. In this perspective, we seek to provide a comprehensive overview of current small-molecule AR degraders and discuss their advantages, disadvantages, and challenges, hoping to provide future directions for the development of novel AR degradation-based therapies for drug-resistant CRPC (Figure ).…”