Cyclin E-Cyclin-dependent kinase 2 complex (Cyclin E-CDK2)

The Cyclin E-Cyclin-dependent kinase 2 (Cyclin E-CDK2) complex is a vital regulator of the eukaryotic cell cycle, specifically governing the transition from the G1 to the S phase (UniProt P24941, P24864). This heterodimeric complex consists of the catalytic subunit CDK2 and a regulatory cyclin partner, either Cyclin E1 or Cyclin E2. Upon activation, the complex phosphorylates various substrates, most notably the Retinoblastoma protein (Rb), which releases E2F transcription factors to trigger the expression of genes required for DNA synthesis (PubMed: 25104308). In many human malignancies, such as breast, ovarian, and lung cancers, the Cyclin E-CDK2 pathway is hyperactivated through CCNE1 gene amplification or protein overexpression. This hyperactivation drives uncontrolled cell proliferation and contributes to resistance against existing therapies like CDK4/6 inhibitors (PubMed: 33067308). Consequently, the complex has emerged as a significant therapeutic target in oncology. Several selective CDK2 inhibitors, including PF-07104091 and BLU-222, are currently undergoing clinical evaluation to treat cyclin E-dependent tumors (ClinicalTrials.gov NCT04553133).

Other names

CCNE1-CDK2 complexCCNE2-CDK2 complexCyclin E1-CDK2Cyclin E2-CDK2

ATP-competitive inhibition of the CDK2 catalytic subunit, preventing the phosphorylation of downstream substrates such as Rb and NPAT, thereby inducing G1/S phase cell cycle arrest (PubMed: 25104308).