The androgen receptor (AR) is a critical therapeutic target for the endocrine treatment of prostate cancer (PCa). Current AR antagonists, which primarily target the hormone binding pocket (HBP) within the ligand-binding domain (LBD), are often limited by the emergence of resistance mutations, calling for novel strategies of AR inhibition. In this study, a series of substituted benzene sulfonamide derivatives were designed and synthesized based on IMB-A6, a lead compound previously identified by our group to target the activation function 2 (AF2) region of AR-LBD. These compounds were evaluated for AR inhibitory activity using a dual-luciferase reporter assay, with selected derivatives further assessed for their anti-proliferative effects against the LNCaP cell line. Notably, compounds 8a and 3l also exhibited significant inhibitory activity against the AR F876L mutant. Additionally, the pharmacokinetic (PK) profile of 8a was evaluated in male Sprague-Dawley (SD) rats. In vivo studies using the LNCaP xenograft model revealed that oral administration of 8a (30 mg/kg, BID) effectively suppressed tumor growth with tumor growth inhibition (TGI) rate of 48.20 %. Molecular docking studies of 8a binding to the AF2 region were conducted. 8a represents the first reported example of an orally effective AR inhibitor derived from AF2-targeting research, offering a promising therapeutic strategy to overcome resistance mutations in PCa treatment.
