Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR

Nat Chem Biol. 2011 Apr 13;7(7):428-30. doi: 10.1038/nchembio.573.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Damage
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • Dose-Response Relationship, Drug
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Humans
  • Molecular Structure
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / genetics
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Sulfones / chemistry
  • Sulfones / pharmacology*
  • Tumor Suppressor Protein p53 / deficiency*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics

Substances

  • 3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Pyrazines
  • Sulfones
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases

Associated data

  • PubChem-Substance/117682505
  • PubChem-Substance/117682506
  • PubChem-Substance/117682507
  • PubChem-Substance/117682508
  • PubChem-Substance/117682509
  • PubChem-Substance/117682510
  • PubChem-Substance/117682511
  • PubChem-Substance/117682512
  • PubChem-Substance/117682513
  • PubChem-Substance/117682514
  • PubChem-Substance/117682515
  • PubChem-Substance/117682516
  • PubChem-Substance/117682517
  • PubChem-Substance/117682518
  • PubChem-Substance/117682519
  • PubChem-Substance/117682520