Discovery of Small-Molecule Inhibitors Selectively Targeting the DNA-Binding Domain of the Human Androgen Receptor

The
human androgen receptor (AR) is considered as a master regulator
in the development and progression of prostate cancer (PCa). As resistance
to clinically used anti-AR drugs remains a major challenge for the
treatment of advanced PCa, there is a pressing need for new anti-AR
therapeutic avenues. In this study, we identified a binding site on
the DNA binding domain (DBD) of the receptor and utilized virtual
screening to discover a set of micromolar hits for the target. Through
further exploration of the most potent hit (1), a structural
analogue (6) was identified demonstrating 10-fold improved
anti-AR potency. Further optimization resulted in a more potent synthetic
analogue (25) with anti-AR potency comparable to a newly
FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated
that the developed inhibitors do interact with the intended target
site. Importantly, the AR DBD inhibitors could effectively inhibit
the growth of Enzalutamide-resistant cells as well as block the transcriptional
activity of constitutively active AR splice variants, such as V7.