Design,Synthesis And Bioassays For Inhibitors Of CDK2-cyclinA2

Nowadays,cancer is one of the main serious diseases affecting human health.Studies have shown that cancer cell-cycle progression is closely related to the expression of Cyclin-dependent kinases.In organisms,the activity of Cdks requires binding of a regulatory subunit,which is called Cyclin.The activating complexes catalyze the phosphorylation of serine or threonine residues on various protein substrates,which accelerate cell cycle period.The cyclin E/CDK2 activating complex drive progression through the G1 phase and the cyclin A/CDK2 activating complex drive progression through the S phase.CDK2 is overexpressed in a great number of tumors,such as gastric cancer,breast cancer,leukemia and lymphoma.Our study aimed at development of CDK inhibitors for basic cancer research.We focused on the ATP binding site of CDK2-cyclin A crystal structures.We obtain a candidate compound after virtual screening and biological assay.Based on the structure and docking model,we synthesize 33 derivatives though the method of pharmaceutical chemistry.It turned out that WZ-026 exhibited high potency towards CDK2-cyclin A,which inhibitory rate was 92.22% at 100μM(IC50 3.81μM).Competition experiment confirmed that the inhibitor was stay in the ATP binding pocket.WZ-026 was selected to conduct a Hep G2 cell proliferation inhibition experiment(IC50 30.58μM).Structure-activity relationship studies at the ATP binding site of a large number of derivatives have established which lay a foundation for the development of new type of CDK2-cyclin A2 inhibitors.