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

Natalya A. Smirnova, Ilay Rakhman, Natalia Moroz, Manuela Basso, Jimmy Payappilly, Sergey Kazakov, Francisco Hernandez-Guzman, Irina N. Gaisina, Alan P. Kozikowski, Rajiv R. Ratan, Irina G. Gazaryan

Research output: Contribution to journalArticle

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-1α 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 HIF1α, upregulate known HIF target genes in a human neuronal line, and exert neuroprotective effects in established model of oxidative stress in cortical neurons.

Original languageEnglish (US)
Pages (from-to)380-391
Number of pages12
JournalChemistry and Biology
Volume17
Issue number4
DOIs
StatePublished - Apr 23 2010

Keywords

  • CELLBIO
  • CHEMBIO
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Fingerprint Dive into the research topics of 'Utilization of an In Vivo Reporter for High Throughput Identification of Branched Small Molecule Regulators of Hypoxic Adaptation'. Together they form a unique fingerprint.

  • Cite this

    Smirnova, N. A., Rakhman, I., Moroz, N., Basso, M., Payappilly, J., Kazakov, S., Hernandez-Guzman, F., Gaisina, I. N., Kozikowski, A. P., Ratan, R. R., & Gazaryan, I. G. (2010). Utilization of an In Vivo Reporter for High Throughput Identification of Branched Small Molecule Regulators of Hypoxic Adaptation. Chemistry and Biology, 17(4), 380-391. https://doi.org/10.1016/j.chembiol.2010.03.008