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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.

Original publication

DOI

10.1016/j.mam.2016.01.001

Type

Journal article

Journal

Mol Aspects Med

Publication Date

02/2016

Volume

47-48

Pages

54 - 75

Keywords

HIF hydroxylases, HIF prolyl hydroxylases, Hypoxia, Hypoxia inducible factor (HIF), Inhibitor, Oxygen sensing, Anemia, Animals, Disease Models, Animal, Drug Delivery Systems, Erythropoietin, Humans, Hypoxia, Hypoxia-Inducible Factor 1, Inflammation, Ischemia, Mixed Function Oxygenases, Oxygen, Prolyl-Hydroxylase Inhibitors, Protein Conformation, Randomized Controlled Trials as Topic