Discovery of novel biphenyl derivatives as androgen receptor degraders for the treatment of enzalutamide-resistant prostate cancer,Bioorganic Chemistry

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Discovery of novel biphenyl derivatives as androgen receptor degraders for the treatment of enzalutamide-resistant prostate cancer
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2024-05-07 , DOI: 10.1016/j.bioorg.2024.107433
Wenqiang Zhang ₁ , Yawen Fan ₁ , Yan Zhang ₂ , Yunrui Feng ₁ , Yi Luo ₁ , Xiaoyu Zhou ₁ , Zhuolin Chen ₁ , Chenxiao Wang ₁ , Tao Lu ₃ , Feng Tang ₄ , Yadong Chen ₁ , Hongmei Li ₁ , Yu Jiao ₁

Affiliation

Second-generation AR antagonists, such as enzalutamide, are the primary therapeutic agents for advanced prostate cancer. However, the development of both primary and secondary drug resistance leads to treatment failures and patient mortality. Bifunctional agents that simultaneously antagonize and degrade AR block the AR signaling pathway more completely and exhibit excellent antiproliferative activity against wild-type and drug-resistant prostate cancer cells. Here, we reported the discovery and optimization of a series of biphenyl derivatives as androgen receptor antagonists and degraders. These biphenyl derivatives exhibited potent antiproliferative activity against LNCaP and 22Rv1 cells. Our discoveries enrich the diversity of small molecule AR degraders and offer insights for the development of novel AR degraders for the treatment of enzalutamide-resistant prostate cancer.

中文翻译：

发现新型联苯衍生物作为雄激素受体降解剂，用于治疗恩杂鲁胺耐药性前列腺癌

第二代AR拮抗剂，例如恩杂鲁胺，是晚期前列腺癌的主要治疗药物。然而，原发性和继发性耐药性的发展导致治疗失败和患者死亡。同时拮抗和降解 AR 的双功能药物可以更完全地阻断 AR 信号通路，并对野生型和耐药性前列腺癌细胞表现出优异的抗增殖活性。在这里，我们报道了一系列作为雄激素受体拮抗剂和降解剂的联苯衍生物的发现和优化。这些联苯衍生物对 LNCaP 和 22Rv1 细胞表现出有效的抗增殖活性。我们的发现丰富了小分子 AR 降解剂的多样性，并为开发用于治疗恩杂鲁胺耐药性前列腺癌的新型 AR 降解剂提供了见解。

更新日期：2024-05-07

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