Discovery of N-(thiazol-2-yl) Furanamide Derivatives as Potent Orally Efficacious AR Antagonists with Low BBB Permeability.
Resistance-conferring mutations in the androgen receptor (AR) ligand-binding pocket (LBP) compromise the effectiveness of clinically approved orthosteric AR antagonists. Targeting the dimerization interface pocket (DIP) of AR presents a promising therapeutic approach. In this study, we report the design and optimization of N-(thiazol-2-yl) furanamide derivatives as novel AR DIP antagonists, among which C13 was the most promising candidate. C13 exhibited excellent AR antagonistic activity (IC50 = 0.010 μM), effectively blocked AR dimerization and nuclear translocation, and demonstrated potent efficacy in several castration-resistant prostate cancer (CRPC) cells. Notably, C13 showed superior efficacy against variant drug-resistant AR mutants, along with favorable metabolic stability, excellent pharmacokinetic properties, and low brain distribution. Furthermore, oral administration of C13 achieved 123.4% tumor growth inhibition in an LNCaP xenograft model without apparent toxicity. As a noncompetitive binder, C13 complements current LBP-targeting AR inhibitors and represents a promising therapy for drug-resistant PCa.