The cytotoxic effect of prexasertib is a consequence of dual inhibition on both CHK1 and AMPK

  • Cell Chem Biol. 2026 Jun 18;33(6):767-784.e7. doi: 10.1016/j.chembiol.2026.04.003.
Jing Guo  1 ,  Ping Wang  1 ,  Wei Liu  1 ,  Xin Shi  1 ,  Wei Wu  1 ,  Xiaoyan Zhang  2 ,  Qiang Chen  3
Affiliations
  • 1. Department of Gastrointestinal Surgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, P.R. China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P.R. China.
  • 2. College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, P.R. China; College of Life Science and Technology, Huazhong Agricultural University, Wuhan, P.R. China. Electronic address: [email protected].
  • 3. Department of Gastrointestinal Surgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, P.R. China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P.R. China; Clinical Medical Research Center of Peritoneal Cancer of Wuhan, Wuhan, P.R. China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China; Hubei Province Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, P.R. China. Electronic address: [email protected].
PMID: 42061410 DOI: 10.1016/j.chembiol.2026.04.003
Abstract

Prexasertib (Prex) is a selective checkpoint kinase 1 and 2 (Chk1/2) inhibitor reported to induce the phosphorylation of AMP-activated protein kinase (AMPK) at threonine 172. However, the mechanism by which Prex regulates AMPK and whether this regulation contributes to Prex sensitivity is unknown. Here, we provide data that suggest that Prex directly binds to the cystathionine β-synthase (CBS) pockets of AMPK complex, leading to increased AMPKα Thr172 phosphorylation via CAMKK2 and LKB1. Intriguingly, Prex also functions as an ATP-competitive inhibitor of AMPK, and prolonged Prex treatment significantly inhibited AMPK in vivo. AMPK depletion enhanced cellular sensitivity to Chk1 inhibition, suggesting that Prex-induced cytotoxicity results from inhibition of Chk1 and AMPK. Exonuclease 1 (Exo1) hyperactivation following combined AMPK and Chk1 inhibition may represent a critical mechanism underlying Prex sensitivity. Our findings revealed an additional role of Prex in AMPK regulation and elucidated the functional significance of AMPK inhibition in Chk1 inhibitor-induced cell death.

Keywords
AMPK; CHK1; CHK1 inhibitor; Exo1; prexasertib.
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