CDK inhibitor

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This article is about the medical therapy. For the cell cycle protein, see Cyclin-dependent kinase inhibitor protein.

A CDK (Cyclin-dependent kinase) inhibitor is a chemical that inhibits the function of CDKs. It is used 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[edit]

In many 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 have revealed that knockout of one specific type of CDK often does not affect proliferation of cells or has 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 periods of the cell cycle. Therefore, the pharmacokinetics and dosing schedule of the candidate compound must be carefully evaulated to maintain active concentration of the drug throughout the entire cell cycle.[4]

Types of CDK inhibitors[edit]

Malumbres et al., categorized CDK inhibitors based on their target specificity;

  • Broad CDK inhibitors ; compounds targeting a broad spectrum of CDKs
  • Specific CDK inhibitors ; compounds targeting a 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[edit]

There are more than 10 CDK inhibitor compounds that have gone through or currently ongoing clinical trials, as of 2009. Most of them are targeting multiple CDKs, but some are targeting specific CDKs. For example, P1446A-05 targets CDK4 and PD-0332991 targets CDK4 and CDK6. All compounds are (as of 2009) either in phase I or phase II trials. Various types of cancers including leukemia, melanoma, solid tumors, and other types are being targeted. 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 Lapenna and Giordano[5] or can be searched from http://www.clinicaltrials.gov
PD-0332991 gave encouraging results in a phase II clinical trial on patients with estrogen-positive, HER2-negative advanced breast cancer.[6] The addition of PD-0332991 to letrozole trebled median time to disease progression to 26.1 months compared with 7.5 months for letrozole alone.

References[edit]

  1. ^ Malumbres, M., and Barbacid, M. (2001). To cycle or not to cycle: a critical decision in cancer. Nature reviews 1, 222-231.
  2. ^ Malumbres, M., and Barbacid, M. (2009). Cell cycle, CDKs and cancer: a changing paradigm. Nature reviews 9, 153-166.
  3. ^ 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.
  4. ^ 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.
  5. ^ Lapenna, S., and Giordano, A. (2009). Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 8, 547-566.
  6. ^ "Novel Agent Extends Breast Cancer Time to Progression". 6 Dec 2012.