The transformation of clinical androgen receptor (AR) antagonists into agonists driven by AR mutations poses a significant challenge in treating prostate cancer (PCa). Novel anti-AR therapeutics combating mutation-induced resistance are required. Herein, by combining structure-based virtual screening and biological evaluation, a high-affinity agonist E10 was first discovered. Then guided by the representative conformation of State 1 at the free energy landscape, the structural optimization of E10 was performed, and pure AR antagonists EL15 (IC₅₀ = 0.94 μM) and EF2 (IC₅₀ = 0.30 μM) were successfully identified. Both can antagonize wild-type and variant drug-resistant ARs. Therein, EF2 demonstrated potent inhibition of the AR pathway and effectively suppressed tumor growth in a C4–2B xenograft mouse model following oral administration. Further molecular dynamics simulation and mutagenesis studies revealed atomic insights into the mode of action of EF2 which may serve as a novel lead compound for developing therapeutics against AR-driven PCa.

中文翻译：

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发现 5-硝基-N-（3-（三氟甲基）苯基）吡啶-2-胺作为抗雄激素耐药的新型纯雄激素受体拮抗剂


临床雄激素受体 （AR） 拮抗剂转化为 AR 突变驱动的激动剂，对治疗前列腺癌 （PCa） 构成了重大挑战。需要对抗突变诱导耐药性的新型抗 AR 疗法。在此，通过结合基于结构的虚拟筛选和生物学评价，首次发现了一种高亲和力激动剂 E10。然后，在状态 1 在自由能景观的代表性构象的指导下，对 E10 进行结构优化，成功鉴定了纯 AR 拮抗剂 EL15 （IC₅₀ = 0.94 μM） 和 EF2 （IC₅₀ = 0.30 μM）。两者都可以拮抗野生型和变体耐药性 AR。其中，EF2 在口服给药后在 C4-2B 异种移植小鼠模型中表现出对 AR 通路的有效抑制并有效抑制肿瘤生长。进一步的分子动力学模拟和诱变研究揭示了对 EF2 作用方式的原子见解，EF2 可能作为开发针对 AR 驱动的 PCa 的疗法的新型先导化合物。