Zhang Bei, Li Yanhong, Lin Yukang, Wang Ting, Chen Lin, Cai Jianfan, Ji Tangyang, Diao Pengcheng, Ma Yufeng, Zhang Yanting, You Wenwei, Chen Jingkao, Zhao Peiliang
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, P. R. China.
J Med Chem. 2025 Jan 23;68(2):1693-1715. doi: 10.1021/acs.jmedchem.4c02441. Epub 2025 Jan 8.
CDK2 and CDK9 play pivotal roles in cell cycle progression and gene transcription, respectively, making them promising targets for cancer treatment. Herein, we discovered a series of -(substituted thiazol-2-yl)--(4-substituted phenyl)pyrimidine-2,4-diamines as highly potent CDK2/9 dual inhibitors. Especially, compound significantly inhibited CDK2 (IC = 0.004 μM) and CDK9 (IC = 0.009 μM), achieving a 1000- and 2800-fold improvement over lead compound , and demonstrating broad antitumor efficacy. Mechanistic studies indicated that effectively and simultaneously suppressed CDK2 and CDK9 proteins in the HCT116 cell line, leading to G2/M cell cycle arrest and cell apoptosis by regulating cell cycle- and apoptosis-related protein expression. Most importantly, exhibited 86.7% oral bioavailability in rats and effectively inhibited tumor growth in HCT116 xenograft and C6 glioma rat models without significant toxicity. Overall, these observations clearly confirmed the promising therapeutic strategy of CDK2/9 dual inhibitors and provided a novel potent candidate for cancer therapy.
细胞周期蛋白依赖性激酶2（CDK2）和细胞周期蛋白依赖性激酶9（CDK9）分别在细胞周期进程和基因转录中发挥关键作用，这使它们成为颇具前景的癌症治疗靶点。在此，我们发现了一系列的 -（取代噻唑-2-基）- -（4-取代苯基）嘧啶-2,4-二胺作为高效的CDK2/9双重抑制剂。特别是，化合物 显著抑制CDK2（IC = 0.004 μM）和CDK9（IC = 0.009 μM），相较于先导化合物 分别实现了1000倍和2800倍的提升，并展现出广泛的抗肿瘤疗效。机制研究表明， 在HCT116细胞系中有效且同时抑制CDK2和CDK9蛋白，通过调节细胞周期和凋亡相关蛋白表达导致G2/M期细胞周期阻滞和细胞凋亡。最重要的是， 在大鼠中表现出86.7%的口服生物利用度，并在HCT116异种移植瘤和C6胶质瘤大鼠模型中有效抑制肿瘤生长，且无明显毒性。总体而言，这些观察结果明确证实了CDK2/9双重抑制剂颇具前景的治疗策略，并为癌症治疗提供了一种新型强效候选药物。
