Checkpoint kinase (CHK) (CHK)

Checkpoint kinases (CHK) are a group of serine/threonine-protein kinases, primarily consisting of CHK1 and CHK2, that play a central role in the DNA damage response (DDR) and cell cycle regulation (Source: UniProt, P30301, O96017). CHK1 is typically activated by the ATR kinase in response to single-stranded DNA and replication stress, while CHK2 is activated by the ATM kinase following double-strand breaks (Source: PubMed, PMID: 21782316). These kinases act as signal transducers that phosphorylate downstream effectors, such as the CDC25 family of phosphatases, to induce cell cycle arrest at the G1/S, S, and G2/M checkpoints, allowing time for DNA repair (Source: PubMed, PMID: 11073547). In many human cancers, the G1 checkpoint is lost due to mutations in the TP53 gene, making the survival of these cells heavily dependent on the CHK1-mediated G2/M checkpoint (Source: PubMed, PMID: 25403715). Consequently, pharmacological inhibition of checkpoint kinases can selectively sensitize cancer cells to DNA-damaging agents or act as a potent monotherapy by forcing cells into premature mitosis and cell death (Source: PubMed, PMID: 30104341). Several small-molecule inhibitors, including prexasertib and SRA737, have entered clinical trials, demonstrating potential in treating various solid tumors and hematologic malignancies (Source: ClinicalTrials.gov).

Other names

CHEKSerine/threonine-protein kinase ChkCell cycle checkpoint kinaseCHK1CHK2

Inhibition of CHK1 and/or CHK2 catalytic activity to abrogate DNA damage-induced cell cycle checkpoints, leading to premature mitotic entry and cell death.