PROTACing the androgen receptor and other emerging therapeutics in prostate cancer.

ABSTRACT

INTRODUCTION: The androgen receptor (AR) is a critical driver of prostate cancer progression, and the advent of androgen receptor pathway inhibitors (ARPIs) has transformed the treatment landscape of metastatic prostate cancer. However, resistance to ARPIs eventually develops via mutations in AR, AR overexpression, and alternative AR signaling which have required novel approaches to target effectively. AREAS COVERED The mechanism of action and early clinical results of proteolysis targeting chimera (PROTAC) agents targeting AR are reviewed. Preclinical and early clinical data for other emerging AR-targeting therapeutics, including dual-action androgen receptor inhibitors (DAARIs) and anitens that target the N-terminal domain of AR, were also identified through literature search for agents which may circumvent resistance through AR splice variants and AR ligand-binding domain mutations. The literature search utilized PubMed to identify articles that were relevant to this review from 2000 to 2024. EXPERT OPINION PROTACs, DAARIs, and anitens represent novel and promising AR-targeting therapeutics that may become an important part of prostate cancer treatment in the future. Elucidating mechanisms of resistance, including ability of these agents to target full length AR, may yield further insights into maximal therapeutic efficacy aimed at silencing AR signaling.