title: Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics.
abstract: Defects in p53 function, which occur frequently in human cancers due to mutations in TP53 or disruptions in the p53 regulatory pathway, render cells dependent on CHK1 (Checkpoint Kinase 1) to activate cell cycle checkpoints. In the presence of DNA damage or replication stress, inhibition of CHK1 leads to "mitotic catastrophe" and cell death in p53-deficient tumors while sparing p53-proficient cells. CHK1 inhibitors sensitize tumors to a variety of DNA-damaging agents or antimetabolites in preclinical models and are being evaluated in early phase clinical trials. In this review, we summarize recent advances and controversies in the development and application of CHK1 inhibitors as cancer therapeutics.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.forename: James W
authors.initials: JW
authors.lastname: Janetka
authors.forename: Helen
authors.initials: H
authors.lastname: Piwnica-Worms
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D000071877:Checkpoint Kinase 1; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1