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.

Original publication

DOI

10.1021/cb400088q

Type

Journal article

Journal

ACS Chem Biol

Publication Date

19/07/2013

Volume

8

Pages

1488 - 1496

Keywords

Animals, Animals, Genetically Modified, Biological Assay, Cell Line, Heterocyclic Compounds, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Inhibitory Concentration 50, Models, Molecular, Molecular Structure, Signal Transduction, Small Molecule Libraries, Zebrafish