Cyclin-dependent kinase 2, Cyclin-dependent kinase 4, Cyclin-dependent kinase 6 (CDK2, CDK4, CDK6)

Cyclin-dependent kinases 2, 4, and 6 are serine/threonine kinases essential for regulating transitions through the cell cycle. CDK4 and CDK6, activated by cyclin D, initiate phosphorylation of retinoblastoma (RB) proteins during the G1 phase, which allows transcription factors driving cell cycle progression to be released. CDK2, in complex with cyclin E or A, controls the G1/S phase transition and DNA replication. Aberrant activation of these kinases—often via increased cyclin D expression, loss of endogenous CDK inhibitors (e.g., p16INK4a), or other oncogenic alterations—permits unchecked proliferation, a hallmark of cancer. Highly selective ATP-competitive inhibitors and allosteric agents targeting CDK4/6 are clinically approved in breast cancer, while CDK2 remains a highly active area of drug development. The activity and regulation of these kinases are coordinated, with regulatory feedback loops and compensatory mechanisms influencing therapeutic response

Other names

CDK2CDK4CDK6cell cycle CDKsG1/S CDKs

Inhibition of CDK4/6 prevents phosphorylation of RB, maintaining cell cycle arrest in G1 phase Inhibition of CDK2 interferes with G1/S transition and DNA synthesis