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-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2,3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC50 = 0.004 μM ([ATP] = 25 μM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb+ cells in the G1-phase of the cell division cycle.