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), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. While there are multiple cyclin/CDK complexes regulating the cell cycle, CDK inhibitors targeting CDK4/6 have been the most successful; four CDK4/6 inhibitors have been FDA approved. No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.

The cell cycle is a highly regulated process governing cell division and is controlled by several cyclins and CDKs. Cyclins phosphorylate CDKs, forming complexes that stabilize them and allow them to enact their function. While cyclins activate CDKs, there are other regulatory molecules that can inhibit their function. Under normal conditions, the activation and inhibition of CDK complexes controls the behavior of the cell at many important cell cycle checkpoints to regulate healthy division. However, this process can become dysregulated, leading to the uncontrolled division of cells known as cancer. In fact, in many human cancers, CDKs are overactive or CDK-inhibiting proteins are not functional. CDK inhibitors as a therapy emerged from the idea that order could be restored to an overreactive cell cycle by inhibiting the CDKs whose activation drives the cell cycle forward. 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.

Another remaining question surrounding CDK inhibitors as a therapy is if certain cancers will evade or be resistant to treatment. One study showed that 20% of the patients being treated for metastatic ER+ HER2-breast cancer did not respond at all to treatment with a CDK4/6 inhibitor due to preexisting mutations allowing the cancer cells to continue proliferating despite treatment with the drug. Other studies have shown this number to be as high as 30%. Another study notes that the usefulness of CDK4/6 in the clinical may be limited by acquired drug resistance. In this study, treatment with CDK4/6 inhibitors in ER+ breast cancer and non-small cell lung carcinoma harboring KRAS mutations resulted in upregulation of cyclin D1, CDK4, and cyclin E1, negating the effects of administering the drug.

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

The current FDA approved drugs are all CDK4/6 inhibitors targeting CDK4 and CDK6, two enzymes that control the cell cycle checkpoint transition checkpoint from the G1 to the S phase of the cell cycle. These cell cycle inhibitors work by inducing cell cycle arrest at G1.

Several drugs have been approved by the US FDA for HR-positive, HER2-negative breast cancer.