Cyclin-dependent kinases 2 and 4 (CDK2/4)

Cyclin-dependent kinases 2 and 4 (CDK2 and CDK4) are essential serine/threonine kinases that orchestrate the transition of cells from the G1 phase to the S phase of the cell cycle (NIH, 2024). CDK4, when activated by D-type cyclins, initiates the phosphorylation and inactivation of the retinoblastoma (Rb) protein, while CDK2 subsequently complexes with E-type cyclins to complete Rb phosphorylation, facilitating DNA replication and S-phase entry (Wikipedia, 2024; ACS, 2024). Dysregulation of these kinases is a frequent driver of uncontrolled cell proliferation in various malignancies, including breast, ovarian, and lung cancers (NIH, 2024). While CDK4/6 inhibitors like palbociclib are established therapies for hormone receptor-positive breast cancer, the compensatory overactivation of CDK2 often leads to acquired drug resistance (MD Anderson, 2023; ASCO, 2022). Consequently, dual inhibition of CDK2 and CDK4 is being explored as a strategy to overcome resistance and provide more comprehensive cell cycle blockade (Drug Target Review, 2026). Clinical development of selective CDK2 inhibitors, such as BLU-222 and PF-07104091, aims to balance therapeutic efficacy with the management of side effects such as myelosuppression and gastrointestinal toxicity (MD Anderson, 2023).

Other names

CDK2CDK4Cell division protein kinase 2Cell division protein kinase 4p33 protein kinasePSK-J3CDKN2CMM3

Inhibition of CDK2 and CDK4 kinase activity, which prevents the phosphorylation of the retinoblastoma (Rb) protein, thereby maintaining Rb in its active, growth-suppressive state and inducing G1 phase cell cycle arrest (NIH, 2024; ACS, 2024).