Cyclin-dependent kinase 4 and Cyclin-dependent kinase 6 (CDK4 and CDK6)

Cyclin-dependent kinase 4 and cyclin-dependent kinase 6 are closely related serine/threonine kinases that are central regulators of cell cycle progression, specifically controlling the transition from the G1 to S phase. They function as catalytic subunits activated by binding to D-type cyclins, forming holoenzyme complexes that phosphorylate the retinoblastoma tumor suppressor protein (Rb), thereby promoting E2F-mediated transcription and cell proliferation[1][2][3][4][7]. Dysregulation of CDK4/6 activity—through amplification, overexpression, loss of negative regulators like p16INK4A, or upregulation of cyclin D1—leads to unchecked cell division and is a hallmark of several cancers[6][9]. Selective small-molecule inhibitors of CDK4/6 represent a major advance in targeted therapy, particularly in HR+/HER2- metastatic breast cancer, inducing durable cell cycle arrest by preventing Rb phosphorylation. While generally tolerable, therapy can be associated with hematologic and gastrointestinal toxicities[3][9][10]. CDK4 and CDK6 are both essential for the proliferation of certain tumor types and are considered prime therapeutic targets in oncology research and drug development.

Other names

Cell division protein kinase 4 (CDK4)Cell division protein kinase 6 (CDK6)CDK4/6 (commonly referenced together)p34PSK-J3 (CDK4)Serine/threonine-protein kinase CDK4Serine/threonine-protein kinase CDK6

ATP-competitive inhibition of kinase activity, Inhibition of Rb phosphorylation, Induction of G1 cell cycle arrest, Restoration of Rb-mediated cell cycle control, Blockade of E2F transcription factor activation, Induction of senescence/apoptosis in tumor cells