title: Radioprotection by hymenialdisine-derived checkpoint kinase 2 inhibitors.
abstract: DNA damage induced by ionizing radiation activates the ataxia telangiectasia mutated pathway, resulting in apoptosis or DNA repair. The serine/threonine checkpoint kinase (Chk2) is an important transducer of this DNA damage signaling pathway and mediates the ultimate fate of the cell. Chk2 is an advantageous target for the development of adjuvant drugs for cancer therapy, because inhibition of Chk2 allows normal cells to enter cell cycle arrest and DNA repair, whereas many tumors bypass cell cycle checkpoints. Chk2 inhibitors may thus have a radioprotective effect on normal cells. We report herein a class of natural product derived Chk2 inhibitors, exemplified by indoloazepine 1, that elicit a strong ATM-dependent Chk2-mediated radioprotection effect in normal cells and p53 wt cells, but not p53 mutant cells (>50% of all cancers). This study represents the first example of a radioprotective effect in human cells other than T-cells and implicates a functional ATM pathway as a requirement for IR-induced radioprotection by this class of Chk2 inhibitors. Several of the hymenialdisine-derived analogues inhibit Chk2 at nanomolar concentrations, inhibit autophosphorylation of Chk2 at Ser516 in cells, and increase the survival of normal cells following ionizing radiation.
authors: Department of Chemistry, Michigan State University, East Lansing, 48824, United States.
authors: Thu N T
authors: TN
authors: Nguyen
authors: Rahman S Z
authors: RS
authors: Saleem
authors: Micah J
authors: MJ
authors: Luderer
authors: Stacy
authors: S
authors: Hovde
authors: R William
authors: RW
authors: Henry
authors: Jetze J
authors: JJ
authors: Tepe
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001381:Azepines / Q000138:chemical synthesis / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D001381:Azepines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53; D012694:Serine; C107079:hymenialdisine; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases