Utilization of an In Vivo Reporter for High Throughput Identification of Branched Small Molecule Regulators of Hypoxic Adaptation Academic Article uri icon

Overview

MeSH Major

  • Catechols
  • Dioxygenases
  • High-Throughput Screening Assays
  • Hypoxia
  • Nuclear Proteins
  • Oxyquinoline

abstract

  • Small molecules inhibiting hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are the focus of drug development efforts directed toward the treatment of ischemia and metabolic imbalance. A cell-based reporter produced by fusing HIF-1 alpha oxygen degradable domain (ODD) to luciferase was shown to work as a capture assay monitoring stability of the overexpressed luciferase-labeled HIF PHD substrate under conditions more physiological than in vitro test tubes. High throughput screening identified novel catechol and oxyquinoline pharmacophores with a "branching motif" immediately adjacent to a Fe-binding motif that fits selectively into the HIF PHD active site in in silico models. In accord with their structure-activity relationship in the primary screen, the best "hits" stabilize HIF1 alpha, upregulate known HIF target genes in a human neuronal line, and exert neuroprotective effects in established model of oxidative stress in cortical neurons.

publication date

  • April 23, 2010

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4327942

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2010.03.008

PubMed ID

  • 20416509

Additional Document Info

start page

  • 380

end page

  • 91

volume

  • 17

number

  • 4