Selective Small Molecule Probes for the Hypoxia Inducible Factor (HIF) Prolyl Hydroxylases

ACS Chem Biol. 2013 Jul 19;8(7):1488-96. doi: 10.1021/cb400088q. Epub 2013 Jun 12.

Abstract

The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-α isoforms are regulated in an oxygen-dependent manner by the activity of the HIF prolyl-hydroxylases (PHD or EGLN enzymes), which are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, we describe biochemical, crystallographic, cellular profiling, and animal studies on PHD inhibitors including selectivity studies using a representative set of human 2OG oxygenases. We identify suitable probe compounds for use in studies on the functional effects of PHD inhibition in cells and in animals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Biological Assay
  • Cell Line
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit / drug effects
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Signal Transduction
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Zebrafish / embryology
  • Zebrafish / genetics

Substances

  • HIF1A protein, human
  • Heterocyclic Compounds
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Small Molecule Libraries
  • EGLN1 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases