Cyclin-dependent kinase inhibitors for treating cancer

Cyclin dependent kinases (Cdks) are essential enzymes for the control of cell cycle progression. Inhibitors of cyclin‐dependent kinases are anticipated to possess therapeutic utility against a wide variety of proliferative diseases, especially cancer. The field of published small molecule Cdk inhibitors is briefly reviewed here as background to a summary of work on a class of pyrido[2,3‐d]pyrimidine Cdk inhibitors. Compounds from this class are described that display potency against cyclin D/Cdk4 up to IC50 = 0.004 μM. Good to moderate selectivity for cyclin D/Cdk4 is also reported for compounds in this structural class. Structure‐activity relationship data are presented for substitution at the C2 and N8 positions and these data are interpreted in the context of a binding model that is based on the Cdk2 crystal structure. A representative cyclin D/Cdk4 inhibitor (compound 56) is demonstrated to selectively inhibit the proliferation of an Rb+ cell line vs. a matched Rb− cell line and to produce a distinct G1 block consistent with cyclin D/Cdk4 inhibition in cells. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 6, 487–498, 2001