Cyclin-dependent kinase 4 and Cyclin-dependent kinase 6 (CDK4/6)

Cyclin-dependent kinase 4 (CDK4) and Cyclin-dependent kinase 6 (CDK6) are serine/threonine kinases that serve as critical gatekeepers of the mammalian cell cycle, specifically regulating the transition from the G1 phase to the S phase (UniProt P11802; UniProt Q00534). These enzymes are activated upon binding to D-type cyclins, forming a catalytic complex that phosphorylates the retinoblastoma (Rb) protein. This phosphorylation event releases E2F transcription factors, which subsequently initiate the transcription of genes required for DNA replication and cell cycle progression (O'Leary et al., 2016, Nature Reviews Clinical Oncology). In many human malignancies, particularly hormone receptor-positive (HR+) breast cancer, the CDK4/6-cyclin D-Rb pathway is frequently hyperactivated, driving uncontrolled cell proliferation. Therapeutic agents targeting the ATP-binding site of these kinases act as competitive inhibitors, effectively blocking their catalytic activity and inducing cell cycle arrest (StatPearls, CDK4/6 Inhibitors). Currently, CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib are standard-of-care treatments for advanced breast cancer, though their use requires monitoring for side effects such as myelosuppression and gastrointestinal distress (FDA Label: Ibrance; FDA Label: Kisqali; FDA Label: Verzenio).

Other names

CDK4CDK6Cell division protein kinase 4Cell division protein kinase 6Serine/threonine-protein kinase CDK4Serine/threonine-protein kinase CDK6Cyclin-dependent kinase 4/6 complex

ATP-competitive inhibition of CDK4 and CDK6 kinases, preventing the phosphorylation of the retinoblastoma (Rb) protein and inducing G1-phase cell cycle arrest.