Potent and selective triazole-based inhibitors of the hypoxia-inducible factor prolyl-hydroxylases with activity in the murine brain

DOI: 10.1371/journal.pone.0132004
PMID: 26147748

Authors: Mun Chiang Chan (University of Oxford) , Onur Atasoylu (University of Oxford) , Emma Hodson (University of Oxford) , Anthony Tumber (University of Oxford) , Ivanhoe K. H. Leung (University of Oxford) , Rasheduzzaman Chowdhury (University of Oxford) , Verónica Gómez-Pérez (University of Oxford) , Marina Demetriades (University of Oxford) , Anna M. Rydzik (University of Oxford) , James Holt-Martyn (University of Oxford) , Ya-Min Tian (University of Oxford) , Tammie Bishop (University of Oxford) , Timothy D. W. Claridge (University of Oxford) , Akane Kawamura (University of Oxford) , Christopher W. Pugh (University of Oxford) , Peter J. Ratcliffe (University of Oxford) , Christopher J. Schofield (University of Oxford) , Sonia Rocha (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos One , VOL 10 (7)

State: Published (Approved)
Published: September 2015

Abstract: As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.

Journal Keywords: Immunoblotting; Hydroxylation; NMR relaxation; Mouse models; Crystal structure; Enzyme-linked immunoassays; Medical hypoxia; Molecular cloning

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 20/11/2015 14:36

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Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Neurology Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)