Discovery and optimization of pyrazolopyrimidine sulfamates as ATG7 inhibitors

Bioorg Med Chem. 2020 Oct 1;28(19):115681. doi: 10.1016/j.bmc.2020.115681. Epub 2020 Aug 4.

Abstract

Autophagy is postulated to be required by cancer cells to survive periods of metabolic and/or hypoxic stress. ATG7 is the E1 enzyme that is required for activation of Ubl conjugation pathways involved in autophagosome formation. This article describes the design and optimization of pyrazolopyrimidine sulfamate compounds as potent and selective inhibitors of ATG7. Cellular levels of the autophagy markers, LC3B and NBR1, are regulated following treatment with these compounds.

Keywords: ATG7; ATG7 inhibitor; Autophagy; E1 enzyme.

MeSH terms

  • Autophagy / drug effects
  • Autophagy-Related Protein 7 / antagonists & inhibitors*
  • Autophagy-Related Protein 7 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Sulfonic Acids / chemical synthesis
  • Sulfonic Acids / chemistry
  • Sulfonic Acids / pharmacology*

Substances

  • Pyrazoles
  • Pyrimidines
  • Sulfonic Acids
  • pyrazolylpyrimidine
  • sulfamic acid
  • ATG7 protein, human
  • Autophagy-Related Protein 7