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

DOI: 10.1039/C7SC02103H

Authors: Tzu-Lan Yeh (Target Discovery Institute (TDI), University of Oxford) , Thomas m. Leissing (Ludwig Institute for Cancer Research, University of Oxford) , Martine I. Abboud (University of Oxford) , Cyrille C. Thinnes (University of Oxford) , Onur Atasoylu (University of Oxford) , James P. Holt-Martyn (University of Oxford) , Dong Zhang (University of Oxford) , Anthony Tumber (Structural Genomics Consortium (SGC), University of Oxford) , Kerstin Lippl (University of Oxford) , Christopher T. Lohans (University of Oxford) , Ivanhoe K. H. Leung (University of Oxford) , Helen Morcrette (Wellcome Trust Centre for Human Genetics) , Ian J. Clifton (University of Oxford) , Timothy D. W. Claridge (University of Oxford) , Akane Kawamura (University of Oxford; Wellcome Trust Centre for Human Genetics) , Emily Flashman (University of Oxford) , Xin Lu (Ludwig Institute for Cancer Research, University of Oxford) , Peter J. Ratcliffe (Target Discovery Institute (TDI), University of Oxford; The Francis Crick Institute) , Rasheduzzaman Chowdhury (University of Oxford) , Christopher W. Pugh (Target Discovery Institute (TDI), University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science , VOL 30

State: Published (Approved)
Published: September 2017
Diamond Proposal Number(s): 12346 , 9306

Abstract: 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.

Diamond Keywords: Anaemia

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 18/10/2017 09:25

Documents:
C7SC02103H.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)