Cyclin-dependent kinase inhibitors: novel anticancer agents.
In current models of cell cycle control, the transition between different cell cycle states is regulated at checkpoints. Transition through the cell-cycle is induced by a family of protein kinase holoenzymes, the cyclin-dependent kinases (CDKs) and their heterodimeric cyclin partner. Orderly progression through the cell-cycle involves co-ordinated activation of the CDKs, which in the presence of an associated CDK-activating kinase, phosphorylate target substrates including members of the 'pocket protein' family. This family includes the product of the retinoblastoma susceptibility gene (the pRb protein) and the related p107 and p130 proteins. Activity of these holoenzymes is regulated by post-translational modification. Phosphorylation of inhibitory sites on a conserved threonine residue within the activation segment is regulated by CDK7/cyclin H, referred to as CDK-activating kinase [1]. In addition, the cdc25 phosphatases activate the CDKs by dephosphorylating their inhibitory tyrosine and threonine phosphorylated residues [2,3]. Among the many roles for endogenous inhibitors (CDKIs), including members of the p21(CIP1/Waf1) family and the p16 family, one role is to regulate cyclin activity. Cellular neoplastic transformation is accompanied by loss of regulation of cell cycle checkpoints in conjunction with aberrant expression of CDKs and/or cyclins and the loss or mutation of the negative regulators (the CDKIs or the pocket protein pRb). One strategy to inhibit malignant cellular proliferation involves inhibiting CDK activity or enhancing function of the CDKI. Novel inhibitors of CDKs showing promise in the clinic include flavopiridol and UCN-01, which show early evidence of human tolerability in clinical trials. This review examines pertinent advances in the field of CDK inhibitors.
Mani
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S
The Albert Einstein Cancer Center, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Chanin 302, 1300 Morris Park Ave., Bronx, New York, 10461, USA.
Wang
C
C
Wu
K
K
Francis
R
R
Pestell
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000502:physiology; D006801:Humans
D000970:Antineoplastic Agents; D016213:Cyclins; D018844:Cyclin-Dependent Kinases