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

Abstract

Prostate cancer (PC), the second most prevalent malignancy in men worldwide, has been proven to depend on the aberrant activation of androgen receptor (AR) signaling. Longterm androgen deprivation for the treatment of PC inevitably leads to castration-resistant prostate cancer (CRPC) in which AR remains a crucial oncogenic driver. Thus, there is an urgent need to develop new strategies to address this unmet medical need. Targeting AR for degradation has recently been in a vigorous development stage, and accumulating clinical studies have highlighted the benefits of AR degraders in CRPC patients. Herein, we provide a comprehensive summary of small-molecule AR degraders with diverse mechanisms of action including proteolysis-targeting chimeras (PROTACs), selective AR degraders (SARDs), hydrophobic tags (HyT), and other AR degraders with distinct mechanisms. Accordingly, their structure− activity relationships, biomedical applications, and therapeutic values are also dissected to provide insights into the future development of promising AR degradation-based therapeutics for CRPC.

A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance

“…Of particular clinical relevance, CHIP has been shown to modulate sensitivity to anti-androgen therapy in advanced PCa ( 81 ). These findings are also important with regard to the current development of proteolysis targeting chimeras as pharmacological alternatives for PCa treatment ( 82 , 83 ).…”

Recent Progress on Microtubule Degradation Agents

“…Notably, some small molecules have been serendipitously discovered that could promote target protein degradation via the ubiquitin proteasome pathway. , Retinoic acid and arsenic trioxide can trigger the degradation of promyelocytic leukemia retinoic acid receptor α oncoprotein . Additionally, selective androgen or estrogen receptor modulators promote the degradation of androgen or estrogen receptors. − MDgAs belong to the family of small molecule degraders and operate via distinct mechanisms compared with traditional MSAs and MDsAs. Conventional MSAs and MDsAs such as taxanes and vinca alkaloids are antimitotic and thus preferentially affect rapidly dividing cells.…”

PROTACs: A novel strategy for cancer drug discovery and development

“…The most representative alternative approach is the development of targeted protein degradation (TPD), with proteolysis targeting chimeras (PROTACs) as a typical example 12–18 . TPD has entered its third decade with both opportunities and challenges 19–28 . TPD techniques rely on the ubiquitin–proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates 29–41 …”

“…[12][13][14][15][16][17][18] TPD has entered its third decade with both opportunities and challenges. [19][20][21][22][23][24][25][26][27][28] TPD techniques rely on the ubiquitin-proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. [29][30][31][32][33][34][35][36][37][38][39][40][41] The concept of PROTAC was first proposed in 2001, and the PROTAC technology has developed rapidly in the past 20 years.…”