Novel Inhibitors of androgen receptor's DNA binding domain identified using an ultra‐large virtual screening

Abstract Androgen receptor (AR) inhibition remains the primary strategy to combat the progression of prostate cancer (PC). However, all clinically used AR inhibitors target the ligand‐binding domain (LBD), which is highly susceptible to truncations through splicing or mutations that confer drug resistance. Thus, there exists an urgent need for AR inhibitors with novel modes of action. We thus launched a virtual screening of an ultra‐large chemical library to find novel inhibitors of the AR DNA‐binding domain (DBD) at two sites: protein‐DNA interface (P‐box) and dimerization site (D‐box). The compounds selected through vigorous computational filtering were then experimentally validated. We identified several novel chemotypes that effectively suppress transcriptional activity of AR and its splice variant V7. The identified compounds represent previously unexplored chemical scaffolds with a mechanism of action that evades the conventional drug resistance manifested through LBD mutations. Additionally, we describe the binding features required to inhibit AR DBD at both P‐box and D‐box target sites.