title: Pharmacological targeting of the HIF hydroxylases--A new field in medicine development.
abstract: In human cells oxygen levels are 'sensed' by a set of ferrous iron and 2-oxoglutarate dependent dioxygenases. These enzymes regulate a broad range of cellular and systemic responses to hypoxia by catalysing the post-translational hydroxylation of specific residues in the alpha subunits of hypoxia inducible factor (HIF) transcriptional complexes. The HIF hydroxylases are now the subject of pharmaceutical targeting by small molecule inhibitors that aim to activate or augment the endogenous HIF transcriptional response for the treatment of anaemia and other hypoxic human diseases. Here we consider the rationale for this therapeutic strategy from the biochemical, biological and medical perspectives. We outline structural and mechanistic considerations that are relevant to the design of HIF hydroxylase inhibitors, including likely determinants of specificity, and review published reports on their activity in pre-clinical models and clinical trials.
authors.affiliation: Centre for Cellular and Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Mun Chiang
authors.initials: MC
authors.lastname: Chan
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: James P
authors.initials: JP
authors.lastname: Holt-Martyn
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom. Electronic address: christopher.schofield@chem.ox.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Centre for Cellular and Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom. Electronic address: pjr@well.ox.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
mesh_terms: D000740:Anemia / Q000188:drug therapy; D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004921:Erythropoietin / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy; D007511:Ischemia / Q000188:drug therapy; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology; D011487:Protein Conformation; D016032:Randomized Controlled Trials as Topic
chemical_list: D051793:Hypoxia-Inducible Factor 1; D064800:Prolyl-Hydroxylase Inhibitors; D004921:Erythropoietin; D006899:Mixed Function Oxygenases; D010100:Oxygen
keywords: HIF hydroxylases; HIF prolyl hydroxylases; Hypoxia; Hypoxia inducible factor (HIF); Inhibitor; Oxygen sensing