Fig. 2: The binding location of AR antagonists and roles in inhibition of AR-mediated transactivation.
From: Second generation androgen receptor antagonists and challenges in prostate cancer treatment
A All of the FDA-approved second-generation AR antagonists bind to the ligand-binding domain (LBD). Potential AR antagonists including proxalutamide (Prox), TRC253, BMS-641988, and SHR3680 bind to the LBD, while EPI-506 and EPI-7386 bind to the N-terminal domain (NTD). Among these AR antagonists, EPI-506 and EPI-7386, darolutamide, proxalutamide, and TRC253 can bind with AR harboring mutations such as F876L. B All of the AR antagonists that bind to the LBD can competitively inhibit DHT binding to AR, as well as AR nuclear translocation and binding to DNA and coactivators. Binding of EPI-506 and EPI-7386 to the NTD of AR can inhibit AR transcriptional activation. Of note, proxalutamide can also repress AR protein expression.
