Photoactivatable Prolyl Hydroxylase 2 Inhibitors for Stabilizing the Hypoxia-Inducible Factor with Light

J Med Chem. 2019 Aug 22;62(16):7583-7588. doi: 10.1021/acs.jmedchem.9b00688. Epub 2019 Jun 25.

Abstract

HIF prolyl hydroxylase 2 (PHD2) inhibitors represent a novel approach for treating HIF-related diseases. This study reports the first application of photoremovable protecting group to the photoactivatable inhibitor (7) of PHD2. It allows the inhibitory activity for PHD2 to be controlled by light irradiation, subsequently stabilizing HIF and promoting expression of the target gene. Light activation to stabilize HIF offers promising potentials for the tissue-specific therapies for HIF-related disease by light irradiation onto target tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Enzyme Stability / radiation effects
  • Erythropoietin / genetics
  • Erythropoietin / metabolism
  • Gene Expression Regulation / radiation effects*
  • HEK293 Cells
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1 / chemistry
  • Hypoxia-Inducible Factor 1 / genetics
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / chemistry
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / chemistry
  • Hypoxia-Inducible Factor-Proline Dioxygenases / genetics
  • Light*
  • Models, Chemical
  • Molecular Structure
  • Prolyl-Hydroxylase Inhibitors / chemistry
  • Prolyl-Hydroxylase Inhibitors / pharmacology*

Substances

  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Prolyl-Hydroxylase Inhibitors
  • Erythropoietin
  • Hypoxia-Inducible Factor-Proline Dioxygenases