Discovery of pyrazolopyrimidine derivatives as novel inhibitors of ataxia telangiectasia and rad3 related protein (ATR)

Bioorg Med Chem Lett. 2017 Feb 15;27(4):750-754. doi: 10.1016/j.bmcl.2017.01.045. Epub 2017 Jan 16.

Abstract

The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K.

Keywords: ATR; DNA damage; HTS; PI3K; Pyrazolopyrimidine.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Drug Evaluation, Preclinical
  • Humans
  • Inhibitory Concentration 50
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Pyridines / chemistry*
  • Pyridines / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism

Substances

  • 1-(4-(methylsulfonyl)phenyl)-3-(1H-pyrrolo(2,3-b)pyridin-5-yl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • pyrazolopyridine
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases