Design, synthesis, and molecular docking study of 3H‐imidazole[4,5‐c]pyridine derivatives as CDK2 inhibitors

• Published in: Archiv der Pharmazie (Weinheim) 2018-06, Vol.351 (6), p.e1700381-n/a
• Main Authors: Wu, Yi‐Zhe, Ying, Hua‐Zhou, Xu, Lei, Cheng, Gang, Chen, Jing, Hu, Yong‐Zhou, Liu, Tao, Dong, Xiao‐Wu
• Format: Article
• Language: English
• Subjects: cancer; CDK2 inhibitor; imidazo[4,5‐c]pyridine; targeted therapy
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201700381

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. Novel imidazo[4,5‐c]pyridine‐based CDK2 inhibitors were designed starting from CYC202 via scaffold hopping and evaluated for their CDK2 inhibitory and in vitro anti‐proliferation activity against cancer cells. Molecular docking shows the potential binding mechanism between the most potent compound 5b and CDK2. The pyridin‐3‐ylmethyl moiety may be an excellent pharmacophore for developing novel CDK2 inhibitors for targeted anticancer therapy.