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Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials

Lookup NU author(s): Professor Akane Kawamura

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2017 The Royal Society of Chemistry. Inhibition of the human 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (human PHD1-3) causes upregulation of HIF, thus promoting erythropoiesis and is therefore of therapeutic interest. We describe cellular, biophysical, and biochemical studies comparing four PHD inhibitors currently in clinical trials for anaemia treatment, that describe their mechanisms of action, potency against isolated enzymes and in cells, and selectivities versus representatives of other human 2OG oxygenase subfamilies. The 'clinical' PHD inhibitors are potent inhibitors of PHD catalyzed hydroxylation of the HIF-α oxygen dependent degradation domains (ODDs), and selective against most, but not all, representatives of other human 2OG dependent dioxygenase subfamilies. Crystallographic and NMR studies provide insights into the different active site binding modes of the inhibitors. Cell-based results reveal the inhibitors have similar effects on the upregulation of HIF target genes, but differ in the kinetics of their effects and in extent of inhibition of hydroxylation of the N- and C-terminal ODDs; the latter differences correlate with the biophysical observations.


Publication metadata

Author(s): Yeh T-L, Leissing TM, Abboud MI, Thinnes CC, Atasoylu O, Holt-Martyn JP, Zhang D, Tumber A, Lippl K, Lohans CT, Leung IKH, Morcrette H, Clifton IJ, Claridge TDW, Kawamura A, Flashman E, Lu X, Ratcliffe PJ, Chowdhury R, Pugh CW, Schofield CJ

Publication type: Article

Publication status: Published

Journal: Chemical Science

Year: 2017

Volume: 8

Issue: 11

Pages: 7651-7668

Print publication date: 01/11/2017

Online publication date: 11/09/2017

Acceptance date: 07/09/2017

Date deposited: 10/10/2019

ISSN (print): 2041-6520

ISSN (electronic): 2041-6539

Publisher: Royal Society of Chemistry

URL: https://doi.org/10.1039/c7sc02103h

DOI: 10.1039/c7sc02103h


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Funding

Funder referenceFunder name
106241/Z/14/Z
C8717/A18245/A16016
BB/J003018/1
BB/L009846/1
EP/G03706X/1
RG/11/28684

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