Cyclin-dependent kinase (CDK) inhibitors are chemicals that inhibit the function of CDKs to treat cancers by preventing overproliferation of cancer cells. Although there is no approved anti-cancer drugs that target CDKs yet, several compounds are on clinical trials now (2009).
CDKs as cancer target
editIn many of human cancers, CDKs are overactive or CDK-inhibiting proteins are not functional[1] [2]. Therefore, it is rational to target CDK function to prevent unregulated proliferation of cancer cells.
However, the validity of CDK as a cancer target should be carefully assessed because genetic studies revealed that knockout of one specific type of CDK often does not affect proliferation of cells or have an effect only in specific tissue types. For example, most adult cells in mice proliferate normally even without both CDK4 and CDK2[3].
Furthermore, specific CDKs are only active in certain period of cell cycle. Therefore, pharmacokinetics and dosing schedule of the candidate compound must be accordingly evaulated to maintain active concentration of the drug throughout the entire cell cycle[4].
Types of CDK inhibitors
editMalumbres et al., categorized CDK inhibitors based on their target specificity;
- Broad CDK inhibitors ; compounds targeting broad spectrum of CDKS
- Specific CDK inhibitors ; compounds targeting specific type of CDK
- Multiple target inhibitors ; compounds targeting CDKs as well as additional kinases such as VEGFR or PDGFR
CDK inhibitors on clinical trials
editThere are more than 10 cdk inhibitor compounds that had gone through or currently ongoing clinical trials. Most of them are targeting multiple CDKs at the same time but some are targeting specific CDKs. For example, P1446A-05 targets CDK4 and PD-0332991 targets CDK4 and CDK6. All compounds are either in phase I or phase II trials. Various types of cancers including leukemia, melanoma, solid tumors, etc are being targeted and in some cases, very specific cancer types such as 'melanoma positive for cyclin D1 expression' are targeted to maximize the efficacy. Further details can be found in the Lapenna and Giordano[5] or can be searched from http://www.clinicaltrials.gov
References
edit- ^ Malumbres, M., and Barbacid, M. (2001). To cycle or not to cycle: a critical decision in cancer. Nature reviews 1, 222-231.
- ^ Malumbres, M., and Barbacid, M. (2009). Cell cycle, CDKs and cancer: a changing paradigm. Nature reviews 9, 153-166.
- ^ Barriere, C., Santamaria, D., Cerqueira, A., Galan, J., Martin, A., Ortega, S., Malumbres, M., Dubus, P., and Barbacid, M. (2007). Mice thrive without Cdk4 and Cdk2. Molecular oncology 1, 72-83.
- ^ Malumbres, M., Pevarello, P., Barbacid, M., and Bischoff, J.R. (2008). CDK inhibitors in cancer therapy: what is next? Trends in pharmacological sciences 29, 16-21.
- ^ Lapenna, S., and Giordano, A. (2009). Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 8, 547-566.