CDK inhibitor
A CDK (cyclin-dependent kinase) inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance),[1] a CDK4/6 inhibitor, in Feb 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. Several compounds are on clinical trials.
CDKs as cancer target
In many human cancers, CDKs are overactive or CDK-inhibiting proteins are not functional.[2][3] 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.[4]
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.[5]
Types of CDK inhibitors
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 approved
Palbociclib (PD-0332991) (inhibitor of CDK4 and CDK6) 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. The FDA granted it Accelerated Approval in Feb 2015.
CDK inhibitors on clinical trials
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. 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.[7]
As of January 2016[update] Abemaciclib (LY2835219) is in two phase 3 trials for breast cancer.
As of March 2016[update] LEE011 is in three phase 3 trials.[8]
References
- ^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432871.htm
- ^ Malumbres, M; Barbacid, M (2001). "To cycle or not to cycle: A critical decision in cancer". Nature Reviews Cancer. 1 (3): 222–31. doi:10.1038/35106065. PMID 11902577.
- ^ Malumbres, M; Barbacid, M (2009). "Cell cycle, CDKs and cancer: A changing paradigm". Nature Reviews Cancer. 9 (3): 153–66. doi:10.1038/nrc2602. PMID 19238148.
- ^ Barrière, C; Santamaría, D; Cerqueira, A; Galán, J; Martín, A; Ortega, S; Malumbres, M; Dubus, P; Barbacid, M (2007). "Mice thrive without Cdk4 and Cdk2". Molecular Oncology. 1 (1): 72–83. doi:10.1016/j.molonc.2007.03.001. PMID 19383288.
- ^ Malumbres, M; Pevarello, P; Barbacid, M; Bischoff, J. R. (2008). "CDK inhibitors in cancer therapy: What is next?". Trends in Pharmacological Sciences. 29 (1): 16–21. doi:10.1016/j.tips.2007.10.012. PMID 18054800.
- ^ "Novel Agent Extends Breast Cancer Time to Progression". 6 Dec 2012.
- ^ Lapenna, S; Giordano, A (2009). "Cell cycle kinases as therapeutic targets for cancer". Nature Reviews Drug Discovery. 8 (7): 547–66. doi:10.1038/nrd2907. PMID 19568282.
- ^ phase 3 trials of CDK inhibitors