Unraveling the Efficacy of AR Antagonists Bearing -(4-(Benzyloxy)phenyl)piperidine-1-sulfonamide Scaffold in Prostate Cancer Therapy by Targeting LBP Mutations.

Point mutations in the androgen receptor (AR) are significant drivers of resistance in prostate cancer (PCa), posing a great challenge to the development of effective treatment strategies. Building on our previous discovery of the suboptimal AR antagonist , we developed , which contains an -(4-(benzyloxy)phenyl)piperidine-1-sulfonamide scaffold through structural optimization and comprehensive screening against T878A-mutated AR. outperformed existing antiandrogens by fully antagonizing clinical AR mutations and effectively suppressing castration- and enzalutamide-resistant LNCaP cells proliferation . Mechanically, was found to disrupt AR nuclear translocation, hinder AR homodimerization, and suppress transcription of AR-regulated genes by competitive binding to the ligand binding pocket. Further experiments demonstrated that significantly reduced both regular- and enzalutamide-resistant LNCaP tumor volume and serum prostate-specific antigen levels in mice. These findings position as a promising and innovative therapeutic for advanced PCa, particularly in cases where resistance to current therapies is a concern.