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 IC50 values of less than 1 µM. The most potent compound 5b showed excellent CDK2 inhibitory (IC50 = 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.

中文翻译：

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3H-咪唑[4,5-c]吡啶衍生物作为CDK2抑制剂的设计、合成和分子对接研究

基于CYC202的结构，通过支架跳跃策略设计了一系列新型咪唑并[4,5-c]吡啶基CDK2抑制剂。这些化合物被合成并进行生物学评估，以评估它们对癌细胞系的 CDK2 抑制和体外抗增殖潜力。几种化合物表现出有效的 CDK2 抑制作用，IC50 值小于 1 µM。最有效的化合物 5b 对三种不同的细胞系（HL60、A549 和 HCT116）显示出优异的 CDK2 抑制（IC50 = 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，并观察到它们之间的几个关键相互作用，这可能是其有效的 CDK2 抑制和抗增殖活性的原因。所以，