The human androgen receptor (AR) is considered as a master regulator in the development and progression of prostate cancer (PCa). As resistance to current antiandrogens remains a major challenge for the treatment of advanced PCa, there is a continuing need to pursue new anti-AR therapeutic avenues. In this study, we identified a plausible binding site on the DNA binding domain (DBD) of the AR, and small-molecule inhibitors through initial screening against this site. Through exploring the related chemical space of a moderately active initial hit compound, an analogue with 10-fold improved activity was identified, and with the preliminary structure-activity relationship (SAR) on this chemical class, we obtained a lead compound of equal potency as current drug Enzalutamide. The site-directed mutagenesis demonstrates the developed inhibitors do interact with the proposed binding site on the AR DBD, suggesting a novel mechanism of action that is fundamentally different from conventional targeting of the AR through its ligand binding domain (LBD). Furthermore, they effectively inhibit the growth of cells with resistance to Enzalutamide and blocks the transcription of constitutively active AR splice variants, which lack the entire LBD and play a critical role in the development of resistance to conventional antiandrogens. The current study provides an initial proof of principle for selectively targeting the AR DBD, which may be a novel and viable approach for the treatment of advanced and resistant PCa.

Targeting androgen receptor DNA-binding domain using structure-based methods to overcome resistance

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.