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 IC(50) = 0.004 microM. 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 G(1) block consistent with cyclin D/Cdk4 inhibition in cells.
Toogood
P L
PL
Department of Medicinal Chemistry, Pfizer Global Research & Development, Ann Arbor Laboratories, Ann Arbor, Michigan 48105, USA. Peter.toogood2@pfizer.com
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases