Discovery of a Novel Androgen Receptor Antagonist Manifesting Evidence to Disrupt the Dimerization of the Ligand-Binding Domain via Attenuating the Hydrogen-Bonding Network Between the Two Monomers.

Androgen receptor (AR) has proved to be a vital drug target for treating prostate cancer. Here, we reported the discovery of a novel AR antagonist targeting the AR ligand-binding pocket, but distinct from the marketed drug enzalutamide (Enz), demonstrated inhibition on the AR ligand-binding domain (LBD) dimerization, which is a novel mechanism reported for the first time. First, a novel hit (, IC = 5.57 μM) was identified through virtual screening based on a theoretical AR LBD dimer bound with the Enz model. Then, guided by molecular modeling, was discovered with 32.7-fold improved AR antagonistic activity (IC = 0.17 μM). Besides showing high bioactivity and safety, can inhibit AR nuclear translocation. Furthermore, inhibited the formation of the AR LBD dimer, possibly through attenuating the hydrogen-bonding network between the two monomers. This interesting finding would pave the way for the discovery of a new class of AR antagonists.