Discovery of Novel Bifunctional Agents as Potent Androgen Receptor Antagonists and Degraders for the Treatment of Enzalutamide-Resistant Prostate Cancer.

Bifunctional agents that simultaneously antagonize and degrade various AR proteins more effectively block the AR signaling pathway, offering a promising strategy for the treatment of mCRPC patients. Herein, we report the discovery and development of a series of small-molecule AR degraders with 3,8-diazabicyclo[3.2.1]octan scaffold. The optimal compound 20i exhibited potent AR antagonistic and degrading activities, effectively overcoming multiple resistance mechanisms and showing significant antiproliferative effects against enzalutamide-resistant PCa cell lines. Moreover, compound 20i exhibited favorable oral pharmacokinetics and a good safety profile. In the 22Rv1 xenograft models, 20i exhibited potent antitumor activity without obvious toxicity. Taken together, these results demonstrated that 20i might be a potential candidate for the treatment of enzalutamide-resistant PCa.