Tang Chunlei, Wang Dong, Wang Huabing, Cui Shengkai, Fan Weizheng, Zhang Yan
School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China.
Chem Biol Drug Des. 2025 Feb;105(2):e70062. doi: 10.1111/cbdd.70062.
Cyclin-dependent kinase 9 (CDK9) is considered as an important target in the research of antitumor drugs. Taking the CDK2/9 inhibitor CYC065 as the positive control and an in-house library compound (64) as the lead compound, four classes of 22 target compounds with 9H purine as the core structure were designed to establish structure-activity relationships (SAR). In general, SAR of 9H purine CDK9 inhibitors is systematically described in this paper, resulting in the discovery of two compounds (B2 and B5) with further research value. After conducting selectivity testing against CDK2/9 kinase, compound B5 demonstrated approximately five-fold greater selectivity towards CDK9-cyclinT1 over CDK2-cyclinE2. This work also provides a reference basis for the subsequent research on CDK9 inhibitors.
细胞周期蛋白依赖性激酶9（CDK9）被认为是抗肿瘤药物研究中的一个重要靶点。以CDK2/9抑制剂CYC065作为阳性对照，以一个内部库化合物（64）作为先导化合物，设计了四类以9H嘌呤为核心结构的22种目标化合物，以建立构效关系（SAR）。总体而言，本文系统地描述了9H嘌呤CDK9抑制剂的构效关系，从而发现了两种具有进一步研究价值的化合物（B2和B5）。在对CDK2/9激酶进行选择性测试后，化合物B5对CDK9-细胞周期蛋白T1的选择性比对CDK2-细胞周期蛋白E2高约五倍。这项工作也为后续CDK9抑制剂的研究提供了参考依据。
