Design,Synthesis And Bioassays For Novel Small Molecule Inhibitors Of CDK2

Tumor is a cell cycle disease and a serious threat to human health.Cyclin-dependent kinases（CDKs）are a class of serine/threonine kinase,which are responsible for the regulation of the cell cycle process.CDK2 plays a key role involved in cell cycle regulation directly.CDK2 is dependent on binding to cyclin E and cyclin A,so that they can regulate the G₁-S transition phase and S phase.Studies have shown that,CDK2 is overexpressed among about 86 percent of cancers.Currently most of CDK2 inhibitors are ATP competitive inhibitors,and the structure is similar to ATP,so that they show low selectivity in CDKs family or other kinases and have toxic side effects.Due to that,to seek efficient and selective CDK2 inhibitor is the urgent problem.The crystal structure of CDK2 provides a basis for rational drug design to target CDK2.The purpose of this study is to find novel small molecule inhibitors of CDK2,including ATP competitive inhibitors and allosteric inhibitors,which will lay the foundation for the subsequent study of selective small molecule inhibitors.This paper uses Computer-Aid Drug Design,chemical synthesis and biological activity testing methods.And we have designed two types of inhibitors with novel structures and different sites of action.We focused on CDK2-cyclin A and CDK2 crystal structures,and purchased a series of compounds after virtual screening on the ATP binding site and the allosteric site.Finally we got the new structures of the lead compounds by testing CDK2 kinase activity in vitro.As for the ATP competitive inhibitors,we optimized the structure of the lead compound to obtain 22 derivatives,it found that CDKI-C018 show good activity(IC₅₀=12.58μM).In addition,we selected CDKI-C018 and CDKI-C015 to conduct a HepG2 cell proliferation inhibition test;As for allosteric inhibitors,S71 and S70 showed good CDK2 inhibitory effects.And the inhibitory rates ware 57.59%and 41.64%respectively at a concentration of 100μM.Moreover,S71 and S70 have a similar chemical structure,which lays the foundation for the further transformation of the CDK2 allosteric inhibitors.