In many human cancers, CDKs are overactive or CDK-inhibiting proteins are not functional. 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. 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 evaluated to maintain active concentration of the drug throughout the entire cell cycle.
Types
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
Approved
gave encouraging results in a phase II clinical trial on patients with hormone receptor -positive, HER2-negative advanced breast cancer. 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 Ribociclib, an inhibitor of CDK4 and CDK6, is US FDA approved in combination with letrozole for treatment of breast cancer in patients with a hormone receptor positive, HER2 negative advanced metastatic breast cancer. A phase three clinical trial found that Ribocyclib administered in combination with letrozole increased the likelihood of progression free survival to 63% in the first 18 months of therapy versus 42% for letrozole alone. Subsequent analysis demonstrated that patients treated with Ribociclib and letrozole showed a median progression-free survival of 25.3 months. Abemaciclib acts as a selective inhibitor for CDK4 and CDK6. In September 2017 the US FDA approved its use for "adult patients who have hormone receptor -positive, human epidermal growth factor receptor 2 -negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones".
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. , Abemaciclib is in two phase 3 trials for breast cancer. In March 2017, Abemaciclib demonstrated superior progression-free survival over placebo plus fulvestrant in patients with estrogen receptor positive and HER2 negative advanced or metastatic breast cancer after the completion of the MONARCH 2 global Phase 3 clinical trial. Ribociclib is in three phase 3 trials for breast cancer. In Oct 2016 good results were reported from the MONALEESA-2 trial in metastatic breast cancer. Trilaciclib,, is in phase 2 clinical trials. e.g. for use to reduce side effects with chemotherapy.
