What are CDK4/6 inhibitor drugs?
CDK4/6 inhibitor drugs are synthetic compounds that help regulate cell proliferation by blocking the activation of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). They are particularly designed for patients with reduced production or function of natural inhibitors from the INK4 protein family. The CDK4/6 inhibitor drugs are commonly used to treat conditions such as HR-positive, HER2-negative breast cancer.
CDK4 and CDK6 are crucial enzymes for DNA replication since they enable the transition from the G1 phase, where the cell growth occurs to the S phase, where the cell is replicated. This transition requires the binding of CDK4 and CDK6 to cyclin D, forming a complex that activates these kinases. Once activated, CDK4 and CDK6 phosphorylate the Rb protein, releasing E2F transcription factors essential for DNA synthesis and repair.
Similarly to natural inhibitors, CDK4/6 inhibitor drugs bind directly to CDK4 and CDK6, preventing their interaction with cyclin D, which suppresses the kinase activation and halts cell division.
CDK4/6 inhibitor drugs list
CDK4/6 inhibitor drugs are specific CDK inhibitors that target cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), in contrast to broad CDK inhibitors, also known as pan-CDK inhibitors, which tend to be less effective. Pan-CDK inhibitor side effects also tend to be more severe.1
The Food and Drug Administration (FDA) in the USA has approved CDK4/6 inhibitors primarily for the treatment of HR-positive, HER2-negative breast cancer. The CDK4/6 inhibitor mechanism of action is typically used in conjunction with other cancer treatments, particularly endocrine therapy and chemotherapy.
Examples of CDK4/6 inhibitor drugs include palbociclib (PD-033299, trade name Ibrance) and ribociclib (LEE011, trade names Kisqali and Kryxana), which have proven effective when combined with the antiestrogen aromatase inhibitor letrozole for treating postmenopausal patients.
Another FDA-approved CDK4/6 inhibitor, abemaciclib (LY2835219, trade name Verzenio), is used with letrozole and other aromatase inhibitors, such as anastrozole and exemestane, as well as with tamoxifen, a selective estrogen receptor modulator (SERM), and fulvestrant, a selective estrogen receptor degrader (SERD).2
The approvals for CDK4/6 inhibitors vary across countries. For instance, dalpiciclib is approved in China for use with fulvestrant.
CDK4/6 inhibitors are not limited to cancer treatment. Trilaciclib (V03AF12, trade name Cosela), another FDA-approved CDK4/6 inhibitor, has been shown to reduce chemotherapy-induced myelosuppression in patients with late-stage small-cell lung cancer (ES-SCLC). Myelosuppression refers to decreased bone marrow activity, which can lead to reduced erythrocyte production, causing anemia, thrombocytopenia (increased bleeding risk), and leukopenia (a weakened immune system).
Additionally, CDK4/6 inhibitors may have potential benefits in treating other health conditions associated with the deregulation of natural CDK4/6 inhibitors, such as neurodegenerative diseases, metabolic disorders, chronic inflammation, and genetic disorders. They may also be beneficial in treating kidney and fibrotic diseases.3
CDK4/6 inhibitor drugs side effects
Inhibitor drugs that target specific CDK enzymes are associated with fewer off-target effects compared to pan-CDK inhibitors, which can exhibit higher toxicity levels. However, they are not entirely free from off-target effects, such as bone marrow suppression. Common side effects include fatigue, nausea, diarrhea, vomiting, skin reactions, headaches, cough, and hair thinning or loss.4
References:
- Kong T et al. “eIF4A Inhibitors Suppress Cell-Cycle Feedback Response and Acquired Resistance to CDK4/6 Inhibition in Cancer.” Molecular Cancer Therapeutics. 2019. 18(11):2158-2170.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132330/ - Stanciu I.-M et al. “An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer—A Systematic Review of Randomized Phase II and III Clinical Trials.” Biomolecules. 2023. 13(9): 1422.
https://www.mdpi.com/2218-273X/13/9/1422 - Liang X.-B et al. “The Therapeutic Potential of CDK4/6 Inhibitors, Novel Cancer Drugs, in Kidney Diseases.” International Journal of Molecular Sciences. 2023. 24(17). 13558.
https://www.mdpi.com/1422-0067/24/17/13558 - “Verzenio + hormone therapy.” Lilly
https://verzenio.lilly.com/early-breast-cancer/what-is-verzenio#verzenio-different