Chen Lin, Zou Zhongkai, Cai Jian Fan, Zeng Wenbin, Zhang Yanting, Liao Yimeng, Zhao Peiliang
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China.
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China.
Eur J Med Chem. 2025 Oct 15;296:117875. doi: 10.1016/j.ejmech.2025.117875. Epub 2025 Jun 14.
Cyclin-dependent kinase 9 (CDK9) is a well-validated target for cancer treatment. In this work, starting from a multitargeted CDK1/2/9 inhibitor ZK304709, optimization efforts successfully led to the discovery of a highly potent selective CDK9 inhibitor 8e which exhibites significant enzyme inhibitory activity (IC = 5.5 nM) which is comparable to that of ZK304709 (IC = 5.0 nM). More importantly, 8e shows high selectivity for CDK9 versus CDK1, CDK2, CDK4, and CDK6, respectively. Additionally, 8e possesses greater or similar antiproliferative efficacy with ZK304709 against HeLa, A549, HCT116, and MCF-7 cells, and exhibits potent in vivo antitumor activity in HCT116 xenograft mouse models with tumor growth inhibition of 59.2 % at 60 mg/kg without obvious signs of toxicity. Research on the mechanism reveals that 8e could concentration-dependently cause the G/M phase arrest and induce cell apoptosis in HCT116 cells. These observations provide a novel tetrahydrothiazolopyridine-based pyrimidine scaffold to further develop selective CDK9 inhibitors for cancer therapy.
细胞周期蛋白依赖性激酶9（CDK9）是一个经过充分验证的癌症治疗靶点。在这项工作中，从多靶点CDK1/2/9抑制剂ZK304709出发，通过优化成功发现了一种高效的选择性CDK9抑制剂8e，其表现出显著的酶抑制活性（IC = 5.5 nM），与ZK304709（IC = 5.0 nM）相当。更重要的是，8e对CDK9相对于CDK1、CDK2、CDK4和CDK6分别表现出高选择性。此外，8e与ZK304709对HeLa、A549、HCT116和MCF-7细胞具有相似或更强的抗增殖效力，并且在HCT116异种移植小鼠模型中表现出有效的体内抗肿瘤活性，在60 mg/kg时肿瘤生长抑制率为59.2%，且无明显毒性迹象。机制研究表明，8e可浓度依赖性地导致HCT116细胞的G/M期阻滞并诱导细胞凋亡。这些观察结果为进一步开发用于癌症治疗的选择性CDK9抑制剂提供了一种基于四氢噻唑并吡啶的新型嘧啶支架。
