State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
J Med Chem. 2022 Sep 22;65(18):12460-12481. doi: 10.1021/acs.jmedchem.2c01164. Epub 2022 Sep 7.
Metastatic castration-resistant prostate cancer (mCRPC) with high mortality has seriously threatened men's health. Bifunctional agents simultaneously degrade and antagonize androgen receptor (AR), display robust AR signaling pathway blockade, and show the therapeutic prospect for mCRPC. Herein, systemic structural modifications on the C-3, C-6, and C-17 positions of galeterone led to the discovery of with the dual functions of AR antagonism and degradation. , exhibited excellent antiproliferative activity and potent AR degradation activity in different PCa cells (LNCaP and 22RV1), as well as outstanding antagonistic activity against wild-type and mutant (W741L, T877A, and F876L) ARs. , effectively inhibited the growth of hormone-sensitive organs in the Hershberger assay and exhibited tumor regression in the enzalutamide-resistant (c4-2b-ENZ) xenograft model. These results confirmed to be a promising AR degrader and antagonist for the treatment of mCRPC patients.
转移性去势抵抗性前列腺癌（mCRPC）死亡率高，严重威胁男性健康。双功能药物可同时降解和拮抗雄激素受体（AR），阻断 AR 信号通路，具有治疗 mCRPC 的前景。本文对 galeterone 的 C-3、C-6 和 C-17 位进行系统结构修饰，发现 具有 AR 拮抗和降解的双重功能。化合物 ，在不同的前列腺癌细胞（LNCaP 和 22RV1）中表现出优异的抗增殖活性和强效的 AR 降解活性，以及对野生型和突变型（W741L、T877A 和 F876L）AR 的拮抗活性。在 Hershberger 测定中， 有效抑制了激素敏感器官的生长，并在恩杂鲁胺耐药（c4-2b-ENZ）异种移植模型中显示出肿瘤消退。这些结果证实 是一种有前途的 AR 降解剂和拮抗剂，可用于治疗 mCRPC 患者。
