Hu Yutong, Li Shuai, Liu Fang, Geng Lv, Shu Xiaohong, Zhang Jian
College of Pharmacy, Dalian Medical University, Dalian 116044, China; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
Bioorg Med Chem Lett. 2015 Oct 1;25(19):4069-73. doi: 10.1016/j.bmcl.2015.08.050. Epub 2015 Aug 20.
Serine/threonine-specific cyclin-dependent kinases (CDKs) are key regulatory elements in eukaryotic cell cycle progression, and the dysregulation of CDKs has been implicated in cancers. Therefore, CDKs have been identified as anti-cancer targets for the development of small-molecule drugs. In this Letter, virtual screening and biological evaluation were performed to identify novel lead structures that allosterically disrupt the interaction between CDK2 and cyclin A3, which are directed toward a noncatalytic binding pocket of CDK2. Ultimately, B2 was identified as exhibiting superior CDK2/cyclin A3 inhibition activity. In addition, our results indicated that B2 exhibited antiproliferative activities against a broad spectrum of human cancer cell lines. Significantly, B2 certainly interrupted the interaction between CDK2 and cyclin A3 and exhibited a concentration-dependent trend. In summary, our results suggest that B2 is the first effective allosteric chemical small-molecule CDK2 inhibitor to be discovered, and further lead optimization may result in a series of novel anti-CDK2 agents.
丝氨酸/苏氨酸特异性细胞周期蛋白依赖性激酶（CDKs）是真核细胞周期进程中的关键调控元件，CDKs的失调与癌症有关。因此，CDKs已被确定为开发小分子药物的抗癌靶点。在本信函中，进行了虚拟筛选和生物学评估，以鉴定新型先导结构，这些结构通过变构作用破坏CDK2与细胞周期蛋白A3之间的相互作用，该相互作用针对CDK2的一个非催化结合口袋。最终，B2被鉴定为具有优异的CDK2/细胞周期蛋白A3抑制活性。此外，我们的结果表明，B2对多种人类癌细胞系表现出抗增殖活性。值得注意的是，B2确实中断了CDK2与细胞周期蛋白A3之间的相互作用，并呈现出浓度依赖性趋势。总之，我们的结果表明，B2是首个被发现的有效的变构化学小分子CDK2抑制剂，进一步的先导优化可能会产生一系列新型抗CDK2药物。
