Zhang Wenqiang, Zhu Hao, Chen Zhuolin, Li Hongmei, Chen Xingru, Fan Yawen, Zhou Xiaoyu, Luo Yi, Zhang Yan, Tang Feng, Zhang Xinhao, Feng Yunrui, Lu Tao, Wei Xian, Chen Yadong, Chen Caiping, Jiao Yu
School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
J Med Chem. 2025 Apr 24;68(8):8330-8345. doi: 10.1021/acs.jmedchem.4c03043. Epub 2025 Apr 15.
Bifunctional agents that simultaneously antagonize and degrade various AR proteins more effectively block the AR signaling pathway, offering a promising strategy for the treatment of mCRPC patients. Herein, we report the discovery and development of a series of small-molecule AR degraders with 3,8-diazabicyclo[3.2.1]octan scaffold. The optimal compound exhibited potent AR antagonistic and degrading activities, effectively overcoming multiple resistance mechanisms and showing significant antiproliferative effects against enzalutamide-resistant PCa cell lines. Moreover, compound exhibited favorable oral pharmacokinetics and a good safety profile. In the 22Rv1 xenograft models, exhibited potent antitumor activity without obvious toxicity. Taken together, these results demonstrated that might be a potential candidate for the treatment of enzalutamide-resistant PCa.
同时拮抗和降解多种雄激素受体（AR）蛋白的双功能药物能更有效地阻断AR信号通路，为治疗转移性去势抵抗性前列腺癌（mCRPC）患者提供了一种有前景的策略。在此，我们报告了一系列具有3,8-二氮杂双环[3.2.1]辛烷骨架的小分子AR降解剂的发现与开发。最优化合物表现出强效的AR拮抗和降解活性，有效克服多种耐药机制，并对恩杂鲁胺耐药的前列腺癌细胞系显示出显著的抗增殖作用。此外，该化合物表现出良好的口服药代动力学和安全性。在22Rv1异种移植模型中，该化合物表现出强效的抗肿瘤活性且无明显毒性。综上所述，这些结果表明该化合物可能是治疗恩杂鲁胺耐药前列腺癌的潜在候选药物。
