title: Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation.
abstract: In response to DNA damage, the ATM protein kinase activates signal transduction pathways essential for coordinating cell cycle progression with DNA repair. In the human disease ataxia-telangiectasia, mutation of the ATM gene results in multiple cellular defects, including enhanced sensitivity to ionizing radiation (IR). This phenotype highlights ATM as a potential target for novel inhibitors that could be used to enhance tumor cell sensitivity to radiotherapy. A targeted compound library was screened for potential inhibitors of the ATM kinase, and CP466722 was identified. The compound is nontoxic and does not inhibit phosphatidylinositol 3-kinase (PI3K) or PI3K-like protein kinase family members in cells. CP466722 inhibited cellular ATM-dependent phosphorylation events and disruption of ATM function resulted in characteristic cell cycle checkpoint defects. Inhibition of cellular ATM kinase activity was rapidly and completely reversed by removing CP466722. Interestingly, clonogenic survival assays showed that transient inhibition of ATM is sufficient to sensitize cells to IR and suggests that therapeutic radiosensitization may only require ATM inhibition for short periods of time. The ability of CP466722 to rapidly and reversibly regulate ATM activity provides a new tool to ask questions about ATM function that could not easily be addressed using genetic models or RNA interference technologies.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rainey
authors.forename: Maura E
authors.initials: ME
authors.lastname: Charlton
authors.forename: Robert V
authors.initials: RV
authors.lastname: Stanton
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kastan
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D006367:HeLa Cells; D006801:Humans; D007259:Infrared Rays; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors*
chemical_list: C532253:2-(6,7-dimethoxyquinazolin-4-yl)-5-(pyridiin-2-yl)-2H-1,2,4-triazol-3-amine; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014230:Triazoles; D025521:Tumor Suppressor Proteins; D016315:Proto-Oncogene Proteins c-abl; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases
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