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Selective Small Molecule Probes for the Hypoxia Inducible Factor (HIF) Prolyl Hydroxylases

DOI: 10.1021/cb400088q DOI Help
PMID: 23683440 PMID Help

Authors: Rasheduzzaman Chowdhury (Department of Chemistry, University of Oxford) , José Ignacio Candela-lena (University of Oxford) , Mun Chiang Chan (University of Oxford) , David Jeremy Greenald (University of Sheffield) , Kar Kheng Yeoh (University of Oxford) , Ya-min Tian (University of Oxford) , Michael A. Mcdonough (University of Oxford) , Anthony Tumber (University of Oxford) , Nathan R. Rose (University of Oxford) , Ana Conejo-garcia (University of Oxford) , Marina Demetriades (University of Oxford) , Sinnakaruppan Mathavan (Genome Institute of Singapore) , Akane Kawamura (University of Oxford) , Myung Kyu Lee (BioNanotechnology Research Center, KRIBB) , Freek Van Eeden (University of Sheffield) , Christopher W. Pugh (University of Oxford) , Peter J. Ratcliffe (University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology , VOL 8 (7) , PAGES 1488 - 1496

State: Published (Approved)
Published: May 2013

Open Access Open Access

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 thefunctional effects of PHD inhibition in cells and in animals.

Journal Keywords: Animals; Genetically; Anoxia; Biological; Cell; Heterocyclic; Humans; Hypoxia-Inducible; alpha; Hypoxia-Inducible; Inhibitory; Models; Molecular; Signal; Small; Zebrafish

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography