Checkpoint kinase 1 and Checkpoint kinase 2 (Chk1/Chk2)

Checkpoint kinase 1 (Chk1) and Checkpoint kinase 2 (Chk2) are critical serine/threonine kinases that function as central mediators of the DNA damage response (DDR) pathway [3, 4]. Activated by upstream kinases ATR and ATM in response to DNA lesions or replication stress, they phosphorylate downstream effectors like Cdc25 phosphatases to induce cell cycle arrest, providing time for DNA repair or initiating apoptosis [6, 11]. In many cancers, the G1 checkpoint is lost due to p53 mutations, making these cells uniquely dependent on Chk1-mediated S and G2 checkpoints to maintain genomic integrity [13]. Therapeutic targeting of Chk1 and Chk2 aims to abrogate these remaining checkpoints, thereby sensitizing tumor cells to DNA-damaging agents or inducing 'synthetic lethality' in cells with high replication stress [7, 12]. Clinical development of Chk1/Chk2 inhibitors, such as prexasertib and AZD7762, has focused on their use as chemosensitizers and as monotherapies in specific genetic backgrounds like BRCA-deficient or p53-mutant tumors [2, 8, 9]. However, challenges remain regarding systemic toxicities, particularly hematologic and cardiac effects, which have impacted the clinical progression of several early candidates [7, 18].

Other names

CHEK1CHEK2Cds1hCds1RAD53LFS2Checkpoint kinase 1Checkpoint kinase 2

ATP-competitive inhibition of Chk1 and Chk2 kinases, leading to the abrogation of DNA damage-induced cell cycle checkpoints (G1/S, intra-S, and G2/M) and the induction of mitotic catastrophe in cancer cells [2, 12].