Checkpoint kinase 1 (CHEK1) and Checkpoint kinase 2 (CHEK2) (CHK1/2)

Checkpoint kinase 1 (CHEK1) and Checkpoint kinase 2 (CHEK2) are essential serine/threonine kinases that orchestrate the cellular response to DNA damage and replication stress (UniProt: O14757, O96017). A primary mechanism by which these kinases enforce the G2/M cell cycle checkpoint is through the phosphorylation of the phosphatase Cdc25C at the Serine 216 (Ser216) residue (PubMed: 9334334). This phosphorylation event creates a binding site for 14-3-3 proteins, which sequester Cdc25C in the cytoplasm, thereby preventing it from entering the nucleus to activate the Cyclin B/Cdk1 complex (PubMed: 9334335). By maintaining Cdc25C in an inactive state, the cell cycle is halted, allowing time for DNA repair before the cell proceeds to mitosis. In many cancers, the G1 checkpoint is lost due to TP53 mutations, making these cells uniquely dependent on the CHK1/2-mediated G2/M checkpoint for survival after genomic insult. Therapeutic inhibition of these kinases prevents the phosphorylation of Cdc25C at Ser216, leading to the premature activation of Cdk1 and forcing cells into mitosis with unrepaired DNA damage. This process, known as mitotic catastrophe, results in selective apoptosis of cancer cells, especially when used in combination with DNA-damaging agents like gemcitabine or cisplatin (ClinicalTrials.gov: NCT02124096). Consequently, CHK1 and CHK2 are significant targets in oncology, with several small-molecule inhibitors currently undergoing clinical evaluation.

Other names

CHEK1CHEK2Chk1Chk2Serine/threonine-protein kinase Chk1Serine/threonine-protein kinase Chk2Cdc25C-regulating kinases

Inhibition of CHK1 and CHK2 prevents the phosphorylation of Cdc25C at Ser216, which normally facilitates G2/M arrest. By blocking this phosphorylation, drugs prevent the sequestration of Cdc25C by 14-3-3 proteins, allowing Cdc25C to activate the Cyclin B/Cdk1 complex prematurely. This leads to mitotic entry despite DNA damage, resulting in mitotic catastrophe and apoptosis, particularly in p53-deficient cells.