Cyclin-dependent kinase inhibitors

Novel anticancer agents

Sridhar Mani, C. Wang, K. Wu, R. Francis, R. Pestell

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1849-1870
Number of pages22
JournalExpert Opinion on Investigational Drugs
Volume9
Issue number8
StatePublished - 2000

Fingerprint

Cyclin-Dependent Kinases
Antineoplastic Agents
Cyclins
Cell Cycle
Holoenzymes
alvocidib
Threonine
Cell Cycle Checkpoints
Cyclin H
Proteins
cdc25 Phosphatases
Retinoblastoma Genes
Post Translational Protein Processing
Protein Kinases
Tyrosine
Phosphorylation
Cell Proliferation
Clinical Trials
Mutation

Keywords

  • Anticancer agents
  • Cyclin-dependent kinase inhibitors
  • Flavopiridol
  • UCN-01

ASJC Scopus subject areas

  • Pharmacology

Cite this

Mani, S., Wang, C., Wu, K., Francis, R., & Pestell, R. (2000). Cyclin-dependent kinase inhibitors: Novel anticancer agents. Expert Opinion on Investigational Drugs, 9(8), 1849-1870.

Cyclin-dependent kinase inhibitors : Novel anticancer agents. / Mani, Sridhar; Wang, C.; Wu, K.; Francis, R.; Pestell, R.

In: Expert Opinion on Investigational Drugs, Vol. 9, No. 8, 2000, p. 1849-1870.

Research output: Contribution to journalArticle

Mani, S, Wang, C, Wu, K, Francis, R & Pestell, R 2000, 'Cyclin-dependent kinase inhibitors: Novel anticancer agents', Expert Opinion on Investigational Drugs, vol. 9, no. 8, pp. 1849-1870.
Mani, Sridhar ; Wang, C. ; Wu, K. ; Francis, R. ; Pestell, R. / Cyclin-dependent kinase inhibitors : Novel anticancer agents. In: Expert Opinion on Investigational Drugs. 2000 ; Vol. 9, No. 8. pp. 1849-1870.
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