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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Biological Assay
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Cell Line
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Heterocyclic Compounds / chemical synthesis*
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacology
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Humans
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Hypoxia
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Hypoxia-Inducible Factor 1, alpha Subunit / drug effects
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
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Inhibitory Concentration 50
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Models, Molecular
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Molecular Structure
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Signal Transduction
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / pharmacology
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Zebrafish / embryology
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Zebrafish / genetics
Substances
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HIF1A protein, human
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Heterocyclic Compounds
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Hypoxia-Inducible Factor 1, alpha Subunit
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Small Molecule Libraries
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EGLN1 protein, human
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Hypoxia-Inducible Factor-Proline Dioxygenases