Cyclin-dependent kinase 2 (CDK2)–cyclin complex (CDK2–cyclin)

Cyclin-dependent kinase 2 (CDK2) is a critical serine/threonine kinase that regulates the eukaryotic cell cycle by forming active complexes with Cyclin E or Cyclin A (UniProt: P24941). The CDK2–Cyclin E complex primarily governs the G1 to S phase transition by phosphorylating the retinoblastoma protein (Rb), while the CDK2–Cyclin A complex is essential for DNA replication and progression through the S phase (PubMed: 32103340). In various malignancies, particularly those with CCNE1 amplification or CDK4/6 inhibitor resistance, CDK2 activity is often dysregulated, leading to aberrant cell proliferation (PubMed: 34534464). Therapeutic strategies targeting CDK2–cyclin complexes involve the development of small-molecule inhibitors that typically compete with ATP for the catalytic binding site. Recent clinical efforts have shifted toward highly selective CDK2 inhibitors, such as PF-07104091 and BLU-222, to avoid the dose-limiting toxicities associated with non-selective pan-CDK inhibition (ClinicalTrials.gov: NCT04553133). These agents are being evaluated for their ability to restore cell cycle control and overcome resistance in solid tumors.

Other names

CDK2Cell division protein kinase 2p33 kinaseCDK2/Cyclin E complexCDK2/Cyclin A complexCDKN2

ATP-competitive inhibition of the CDK2 catalytic subunit, preventing the phosphorylation of downstream substrates such as the retinoblastoma (Rb) protein and E2F-mediated transcription.