title: Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR.
abstract: Here we report a comprehensive biological characterization of a potent and selective small-molecule inhibitor of the DNA damage response (DDR) kinase ATR. We show a profound synthetic lethal interaction between ATR and the ATM-p53 tumor suppressor pathway in cells treated with DNA-damaging agents and establish ATR inhibition as a way to transform the outcome for patients with cancer treated with ionizing radiation or genotoxic drugs.
authors.affiliation: Vertex Pharmaceuticals (Europe), Abingdon, Oxfordshire, UK.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Reaper
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Griffiths
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Long
authors.forename: Jean-Damien
authors.initials: JD
authors.lastname: Charrier
authors.forename: Somhairle
authors.initials: S
authors.lastname: Maccormick
authors.forename: Peter A
authors.initials: PA
authors.lastname: Charlton
authors.forename: Julian M C
authors.initials: JM
authors.lastname: Golec
authors.forename: John R
authors.initials: JR
authors.lastname: Pollard
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: C560580:3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011719:Pyrazines; D013450:Sulfones; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases