Small-Molecule Inhibition of Androgen Receptor Dimerization as a Strategy against Prostate Cancer

The clinically used androgen receptor (AR) antagonists
for the
treatment of prostate cancer (PCa) are all targeting the AR ligand
binding pocket (LBP), resulting in various drug-resistant problems.
Therefore, a new strategy to combat PCa is urgently needed. Enlightened
by the gain-of-function mutations of androgen insensitivity syndrome,
we discovered for the first time small-molecule antagonists toward
a prospective pocket on the AR dimer interface named the dimer interface
pocket (DIP) via molecular dynamics (MD) simulation, structure-based
virtual screening, structure–activity relationship exploration,
and bioassays. The first-in-class antagonist M17-B15 targeting the
DIP is capable of effectively disrupting AR self-association, thereby
suppressing AR signaling. Furthermore, M17-B15 exhibits extraordinary
anti-PCa efficacy in vitro and also in mouse xenograft tumor models,
demonstrating that AR dimerization disruption by small molecules targeting
the DIP is a novel and valid strategy against PCa.