Checkpoint kinase (CHK)

Checkpoint kinases, primarily Checkpoint kinase 1 (CHEK1) and Checkpoint kinase 2 (CHEK2), are critical serine/threonine kinases that regulate the cellular response to DNA damage (UniProt O14757, O96017). They function as signal transducers in the DNA damage response (DDR) pathway, acting downstream of the sensor kinases ATM and ATR to coordinate cell cycle checkpoints and DNA repair (PubMed: 18645335). In the presence of irreparable genomic stress, these kinases facilitate the induction of the mitochondrial apoptotic pathway, a process regulated by the BCL-2 family of proteins that leads to mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation (PMC3504831). The activation of the mitochondrial apoptotic pathway by these kinases involves the modulation of pro-apoptotic proteins like BAX and BAK, leading to the release of cytochrome c and the activation of executioner caspases. Many tumor cells lack a functional G1 checkpoint due to p53 mutations, making them highly dependent on the CHK1-mediated G2/M checkpoint to prevent premature mitosis with damaged DNA (PMC5423212). Pharmacological inhibition of checkpoint kinases exploits this dependency, forcing cancer cells into mitotic catastrophe and triggering intrinsic apoptosis. Clinical development of CHK inhibitors, such as prexasertib and SRA737, focuses on their use as chemosensitizers or as monotherapy in tumors with specific DDR deficiencies.

Other names

CHEK1CHEK2Checkpoint kinase 1Checkpoint kinase 2DNA damage checkpoint kinaseMitochondrial apoptotic pathway / checkpoint kinases

Inhibition of checkpoint kinases (primarily CHK1) prevents DNA damage-induced cell cycle arrest, leading to premature mitotic entry and the induction of the mitochondrial apoptotic pathway in tumor cells.