Design,synthesis, and molecular docking study of 3H‐imidazole[4,5‐c]pyridine derivatives as CDK2 inhibitors |
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| Authors: | Yi‐Zhe Wu Hua‐Zhou Ying Lei Xu Gang Cheng Jing Chen Yong‐Zhou Hu Tao Liu Xiao‐Wu Dong |
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| Institution: | 1. 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;2. School of Life Science and Technology, ShanghaiTech University, Shanghai, P. R. China;3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China;4. College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, P. R. China |
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| Abstract: | A novel series of imidazo4,5‐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. |
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| Keywords: | cancer CDK2 inhibitor imidazo[4 5‐c]pyridine targeted therapy |
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