Discovery of N -(4-(Benzyloxy)-phenyl)-sulfonamide Derivatives as Novel Antagonists of the Human Androgen Receptor Targeting the Activation Function 2.

Androgen receptor (AR) antagonists have been widely used for the treatment of prostate cancer (PCa). As a link between the AR and its transcriptional function, the activation function 2 (AF2) region has recently been revealed as a novel targeting site for developing AR antagonists. Here, we reported a series of N -(4-(benzyloxy)-phenyl)-sulfonamide derivatives as new-scaffold AR antagonists targeting the AR AF2. Therein, compound T1-12 showed excellent AR antagonistic activity (IC ₅₀ = 0.47 μM) and peptide displacement activity (IC ₅₀ = 18.05 μM). Furthermore, the in vivo LNCaP xenograft study confirmed that T1-12 offered effective inhibition on tumor growth when administered intratumorally. The study represents the first successful attempt to identify a small molecule targeting the AR AF2 with submicromolar AR antagonistic activity by structure-based virtual screening and provides important clues for the development of novel therapeutics for PCa treatment.