Checkpoint kinase 1 and 2 (CHK1/2)

Checkpoint kinases, specifically Checkpoint kinase 1 (CHK1) and Checkpoint kinase 2 (CHK2), are essential serine/threonine-protein kinases that coordinate the cellular response to DNA damage and replication stress. They function as critical downstream effectors of the ATM and ATR signaling pathways, phosphorylating substrates such as the CDC25 phosphatase family to induce cell cycle arrest, which allows time for DNA repair or triggers apoptosis if the damage is irreparable (1.1.1, 1.2.1). In oncology, these kinases are significant therapeutic targets because many cancer cells lack a functional G1 checkpoint—often due to TP53 mutations—and become heavily reliant on the S and G2 checkpoints mediated by CHK1 to survive DNA-damaging treatments (1.1.2, 1.2.3). Inhibiting checkpoint kinases can "abrogate" these remaining checkpoints, forcing cancer cells into premature mitosis with unrepaired DNA, which leads to mitotic catastrophe and cell death (1.1.5). While several CHK inhibitors have been investigated in clinical trials, often in combination with chemotherapy or radiotherapy to enhance their efficacy, challenges such as hematologic toxicity and the need for precise patient selection via biomarkers like p53 status remain central to their clinical development (1.2.1, 1.3.1).

Other names

CHEK1CHEK2Chk1Chk2Cell cycle checkpoint kinaseSerine/threonine-protein kinase Chk1Serine/threonine-protein kinase Chk2

Inhibition of kinase activity to abrogate cell cycle checkpoints (S and G2/M), preventing DNA repair and forcing cells into mitotic catastrophe.