Discovery of 5-Nitro--(3-(trifluoromethyl)phenyl) Pyridin-2-amine as a Novel Pure Androgen Receptor Antagonist against Antiandrogen Resistance.

The transformation of clinical androgen receptor (AR) antagonists into agonists driven by AR mutations poses a significant challenge in treating prostate cancer (PCa). Novel anti-AR therapeutics combating mutation-induced resistance are required. Herein, by combining structure-based virtual screening and biological evaluation, a high-affinity agonist was first discovered. Then guided by the representative conformation of State 1 at the free energy landscape, the structural optimization of was performed, and pure AR antagonists (IC = 0.94 μM) and (IC = 0.30 μM) were successfully identified. Both can antagonize wild-type and variant drug-resistant ARs. Therein, demonstrated potent inhibition of the AR pathway and effectively suppressed tumor growth in a C4-2B xenograft mouse model following oral administration. Further molecular dynamics simulation and mutagenesis studies revealed atomic insights into the mode of action of which may serve as a novel lead compound for developing therapeutics against AR-driven PCa.