ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, P. R. China.
Arch Pharm (Weinheim). 2018 Jun;351(6):e1700381. doi: 10.1002/ardp.201700381. Epub 2018 Apr 30.
A novel series of imidazo[4,5-c]pyridine-based CDK2 inhibitors were designed from the structure of CYC202 via scaffold hopping strategy. These compounds were synthesized and biologically evaluated for their CDK2 inhibitory and in vitro anti-proliferation potential against cancer cell lines. Several compounds exhibited potent CDK2 inhibition with IC values of less than 1 µM. The most potent compound 5b showed excellent CDK2 inhibitory (IC = 21 nM) and in vitro anti-proliferation activity against three different cell lines (HL60, A549, and HCT116). The molecular docking and dynamic studies portrayed the potential binding mechanism between 5b and CDK2, and several key interactions between them were observed, which would be the reason for its potent CDK2 inhibitory and anti-proliferation activities. Therefore, the pyridin-3-ylmethyl moiety would serve as an excellent pharmacophore for the development of novel CDK2 inhibitors for targeted anti-cancer therapy.
受 CYC202 结构启发，通过骨架跃迁策略，我们设计了一系列新型的咪唑并[4,5-c]吡啶基 CDK2 抑制剂。我们合成了这些化合物，并对其 CDK2 抑制活性和体外抗癌细胞系增殖活性进行了生物学评价。一些化合物表现出很强的 CDK2 抑制活性，IC 值低于 1 μM。最有效的化合物 5b 对三种不同的细胞系（HL60、A549 和 HCT116）具有优异的 CDK2 抑制作用（IC = 21 nM）和体外抗增殖活性。分子对接和动力学研究描绘了 5b 与 CDK2 之间的潜在结合机制，观察到它们之间的几个关键相互作用，这可能是其具有很强的 CDK2 抑制和抗增殖活性的原因。因此，吡啶-3-基甲基部分可以作为开发新型 CDK2 抑制剂的理想药效团，用于靶向抗癌治疗。
