Cyclin-dependent kinase inhibitors: novel anticancer agents

In current models of cell cycle control, the transition between different c ell cycle states is regulated at checkpoints. Transition through the cell-c ycle is induced by a family of protein kinase holoenzymes, the cyclin-depen dent kinases (CDKs) and their heterodimeric cyclin partner. Orderly progres sion through the cell-cycle involves co-ordinated activation of the CDKs, w hich in the presence of an associated CDK-activating kinase, phosphorylate target substrates including members of the 'pocket protein' family. This fa mily includes the product of the retinoblastoma susceptibility gene (the pR b protein) and the related p107 and p130 proteins. Activity of these holoen zymes is regulated by post-translational modification. Phosphorylation of i nhibitory sites on a conserved threonine residue within the activation segm ent is regulated by CDK7/cyclin H, referred to as CDK-activating kinase [1] . In addition, the cdc25 phosphatases activate the CDKs by dephosphorylatin g their inhibitory tyrosine and threonine phosphorylated residues [2,3]. Am ong the many roles for endogenous inhibitors (CDKIs), including members of the p21(CIP1/Waf1) family and the p16 family, one role is to regulate cycli n activity. Cellular neoplastic transformation is accompanied by loss of re gulation 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 ce llular proliferation involves inhibiting CDK activity or enhancing function of the CDKI. Novel inhibitors of CDKs showing promise in the clinic includ e 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.