Yang Jianzhang, Chang Yu, Zhou Kaijie, Huang Weixue, Tien Jean Ching-Yi, Zhang Pujuan, Liu Wenyan, Zhou Licheng, Zhou Yang, Ren Xiaomei, Mannan Rahul, Mahapatra Somnath, Zhang Yuping, Hamadeh Rudana, Ervine Grafton, Wang Zhen, Wang George Xiaoju, Chinnaiyan Arul M, Ding Ke
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China.
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511400, China.
J Med Chem. 2025 Mar 27;68(6):6718-6734. doi: 10.1021/acs.jmedchem.5c00127. Epub 2025 Mar 13.
Cyclin-dependent kinases 12 and 13 (CDK12/13) have emerged as promising therapeutic targets for castration-resistant prostate cancer (CRPC) and other human cancers. Despite the development of several CDK12/13 inhibitors, challenges remain in achieving an optimal balance of potency, selectivity and pharmacokinetic properties. Here, we report the discovery of , a novel, potent and highly selective covalent inhibitor of CDK12/13 with reasonable pharmacokinetic profiles. effectively inhibited CDK12 and CDK13 with IC values of 39.5 and 26.4 nM, respectively, while demonstrating high selectivity over other CDKs. Mass spectrometry analysis, cocrystal structure determination, and pulldown-proteomic experiments confirmed the compound's covalent binding mode with CDK12/13. Functionally, efficiently suppressed the transcription of DNA damage response genes, induced DNA damage, and triggered apoptosis. Moreover, the compound significantly inhibited the proliferation of multiple tumor cell lines, particularly prostate cancer cells. Notably, exhibited synergistic effects with Akt inhibitors both in vitro and in vivo.
细胞周期蛋白依赖性激酶12和13（CDK12/13）已成为去势抵抗性前列腺癌（CRPC）和其他人类癌症有前景的治疗靶点。尽管已开发出几种CDK12/13抑制剂，但在实现效力、选择性和药代动力学性质的最佳平衡方面仍存在挑战。在此，我们报告了一种新型、强效且高度选择性的CDK12/13共价抑制剂的发现，其具有合理的药代动力学特征。该抑制剂分别以39.5和26.4 nM的IC值有效抑制CDK12和CDK13，同时对其他细胞周期蛋白依赖性激酶表现出高选择性。质谱分析、共晶体结构测定和下拉蛋白质组学实验证实了该化合物与CDK12/13的共价结合模式。在功能上，该抑制剂有效抑制DNA损伤反应基因的转录，诱导DNA损伤并引发细胞凋亡。此外，该化合物显著抑制多种肿瘤细胞系的增殖，尤其是前列腺癌细胞。值得注意的是，该抑制剂在体外和体内均与Akt抑制剂表现出协同作用。
