Comparative Activity and Off-Target Effects in Cells of the CHK1 Inhibitors MK-8776, SRA737, and LY2606368.

ABSTRACT: DNA damage activates the checkpoint protein CHK1 to arrest cell cycle progression, providing time for repair and recovery. Consequently, inhibitors of CHK1 (CHK1i) enhance damage-induced cell death. Additionally, CHK1i elicits single agent cytotoxicity in some cell lines. We compared three CHK1i that have undergone clinical trials and exhibited different toxicities. Each CHK1i inhibits other targets at higher concentrations, and whether these contribute to the toxicity is unknown. We compared their sensitivity in a panel of cell lines, their efficacy at inhibiting CHK1 and CHK2, and their ability to induce DNA damage and abrogate damage-induced S phase arrest. Published in vitro kinase analyses were a poor predictor of selectivity and potency in cells. LY2606368 was far more potent at inhi

SUBMITTER: Ditano JP 

PROVIDER: S-EPMC8033610 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature