Design,Synthesis,activity Evaluation And Structure-activity Relationship Of Small Molecule Inhibitors Targeting CDK6

Cyclin-dependent kinases?CDKs?are a group of proteins that regulate cell cycle,participate in transcriptional regulation,and repair DNA damage,and belong to the serine/threonine kinase family.CDK6,together with cyclin D3,regulates the cell cycle from the G1 phase to the S phase.D3-CDK6 is a component of the core mechanism that drives cell proliferation.Abnormal expression of CDK6 can be observed in many tumor cells.Therefore,CDK6 is an attractive target for development of anti-cancer drugs.We used N-?5-?4-methylpiperazin-1-yl?pyridin-2-yl?pyrimidin-2-amine as the lead compoundandcompletedthedesignandsynthesisofaseriesof N-?pyridin-2-yl?pyrimidin-2-amine derivatives as selective CDK6 inhibitors.Among the 54 compounds synthesized,we found that compound A14 is able to selectively inhibit CDK6 with an IC₅₀0 value of 0.015?M.A14 showed good anti-tumor activity when tested in a panel of tumor cell lines with high expression of CDK6,the results clearly suggest that compound A14 works much better than palbociclib which is a selective CDK6 inhibitor in vitro.Further cell cycle test showed that A14 could block the tumor cell cycle in G0/G1 phase,and ROS level test showed that A14 could increase the level of ROS,but the effect of A14 on inducing apoptosis of tumor cells was not significant.The docking result revealed multiple key interactions between compound A14 and CDK6.In conclusion,compound A14 is a potent CDK6 inhibitor that can be used to further develop highly efficient,highly selective CDK6 inhibitors.