A novel small-molecule androgen receptor antagonist selective for the T878A-mutant AR in prostate cancer therapy.

Prostate cancer (PCa) is one of the most prevalent malignancies in males. While androgen receptor (AR) antagonists play a crucial role in PCa therapy, their efficacy is often limited by resistance arising from AR mutations. Here, we identified S-94, corresponding to the S-enantiomer of compound 94, as a novel AR antagonist with marked selectivity for the T878A-mutant AR. In vitro, S-94 inhibited AR transcriptional activity (IC50 = 0.38 μM) and suppressed cell proliferation (IC50 = 10.32 μM) in LNCaP cells harboring the T878A-mutant AR, while exhibiting lower cytotoxicity toward non-cancerous cells. In vivo, S-94 (20 mg/kg, i.p.) inhibited tumor growth in an LNCaP xenograft model. Mechanistic studies showed that S-94 selectively targeted the T878A-mutant AR, exhibiting 50-fold greater potency against ART878A (IC50 = 0.49 μM) than against wild-type AR (IC50 = 27.18 μM). Moreover, S-94 antagonized several clinically relevant T878A-associated AR mutants, including ARF877L/T878A and ARH875Y/T878A, and displayed high selectivity over GR, MR, and PR. In summary, the study suggests that S-94 targets the T878A-mutant AR as a selective AR antagonist with limited impact on the physiological wild-type AR, and effectively antagonizes clinically relevant T878A-associated AR mutants. These properties highlight S-94 as a promising and potentially safer lead compound for the treatment of prostate cancers harboring T878A-associated AR mutations.