Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases.

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.

• Authors: Rasheduzzaman Chowdhury, José Ignacio Candela-Lena, Mun Chiang Chan, David Jeremy Greenald, Kar Kheng Yeoh, Ya-Min Tian, Michael A McDonough, Anthony Tumber, Nathan R Rose, Ana Conejo-Garcia, Marina Demetriades, Sinnakaruppan Mathavan, Akane Kawamura, Myung Kyu Lee, Freek van Eeden, Christopher W Pugh, Peter J Ratcliffe, Christopher J Schofield
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 8 Issue 7 Pg. 1488-96 (Jul 19 2013) ISSN: 1554-8937 [Electronic] United States
• PMID: 23683440 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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