Androgen receptor (AR) is a crucial driver of prostate cancer (PCa), but acquired resistance to AR antagonists significantly undermines their clinical efficacy. We previously discovered coumarin derivative 1, which is capable of disrupting AR ligand-binding domain dimers, offering the potential for overcoming resistance. However, its poor oral bioavailability limited further development. In this study, comprehensive structure optimizations led to compound 4a (IC₅₀ = 0.051 μM), which exhibited comparable AR antagonistic activity to enzalutamide (IC₅₀ = 0.060 μM) and demonstrated excellent selectivity over other nuclear receptors in vitro. Especially, 4a showed superior efficacy against AR^F876L/T877A and AR^W741C mutants compared to darolutamide and enzalutamide. Moreover, 4a exhibited favorable pharmacokinetic profiles (F = 66.24%) in vivo and significant tumor growth inhibition in an LNCaP xenograft mouse model upon oral administration. These results highlight the potential of 4a as a promising oral AR antagonist for overcoming drug resistance in PCa.

中文翻译：

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鉴定口服生物可利用的香豆素衍生物作为靶向前列腺癌的潜在 AR 拮抗剂


雄激素受体 （AR） 是前列腺癌 （PCa） 的关键驱动因素，但对 AR 拮抗剂的获得性耐药显着破坏了其临床疗效。我们之前发现了香豆素衍生物 1，它能够破坏 AR 配体结合结构域二聚体，为克服耐药性提供了潜力。然而，其较差的口服生物利用度限制了进一步的发展。在这项研究中，全面的结构优化导致了化合物 4a （IC₅₀ = 0.051 μM），其表现出与恩杂鲁胺相当的 AR 拮抗活性 （IC₅₀ = 0.060 μM），并且在体外表现出优于其他核受体的选择性。特别是，与 darolutamide 和 enzalutamide 相比，4a 对 AR^F876L/T877A 和 AR^W741C 突变体表现出优异的疗效。此外，4a 在体内表现出良好的药代动力学特征 （F = 66.24%），口服给药后在 LNCaP 异种移植小鼠模型中表现出显着的肿瘤生长抑制。这些结果突出了 4a 作为一种有前途的口服 AR 拮抗剂克服 PCa 耐药的潜力。