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Cyclin-dependent kinase inhibitors: novel anticancer agents
1The 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.
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.
Insights
Cyclin-dependent kinases (CDKs) control cell cycle progression. Inhibiting CDK activity is a promising strategy against cancer, with novel inhibitors like flavopiridol showing early clinical promise.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Cell cycle progression is regulated by checkpoints and driven by cyclin-dependent kinases (CDKs) complexed with cyclins.
- CDK activity is modulated by phosphorylation, dephosphorylation (by CDK-activating kinase and cdc25 phosphatases), and cyclin-dependent kinase inhibitors (CDKIs).
- Dysregulation of cell cycle control, including aberrant CDK/cyclin expression and loss of negative regulators like pRb, is a hallmark of cancer.
Purpose of the Study:
- To review recent advances in the field of cyclin-dependent kinase (CDK) inhibitors.
- To discuss the role of CDK inhibitors as a therapeutic strategy for malignant cellular proliferation.
Main Methods:
- Literature review of pertinent advances in CDK inhibitor research.
- Examination of the mechanisms of cell cycle regulation by CDKs, cyclins, and CDKIs.
- Discussion of clinical trial data for novel CDK inhibitors.
Main Results:
- Cellular neoplastic transformation is associated with loss of cell cycle checkpoint regulation.
- Inhibiting CDK activity or enhancing CDKI function represents a viable strategy to combat cancer.
- Novel CDK inhibitors, such as flavopiridol and UCN-01, are demonstrating early clinical tolerability.
Conclusions:
- Targeting CDKs offers a promising therapeutic avenue for cancer treatment.
- Continued research into CDK inhibitors is crucial for developing effective anti-cancer therapies.
- The development of novel CDK inhibitors shows potential for clinical application in oncology.