Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases

The identification of 8-ethyl-2-phenylamino-8H-pyrido [2,3-d] pyrimidin-7-o ne (1) as an inhibitor of Cdk4 led to the initiation of a program to evalua te related pyrido [2,3-d]pyrimidin-7-ones for inhibition of cyclin-dependen t kinases (Cdks). Analysis of more than 60 analogues has identified some cl ear SAR trends that may be exploited in the design of more potent Cdk inhib itors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC50 = 0.004 muM([ATP] = 25 muM). X-ray crystallographic analysis of r epresentative compounds bound to the related kinase, Cdk2, reveals that the y occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb(+) cells in the G(1)-phase of the cell division cycle.