Pharmacological targeting of the HIF hydroxylases - A new field in medicine development

被引：110

作者：

Chan, Mun Chiang ^{[1
]}

Holt-Martyn, James P. ^{[2
]}

Schofield, Christopher J. ^{[2
]}

Ratcliffe, Peter J. ^{[1
]}

机构：

[1] Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Roosevelt Dr, Oxford OX3 7BN, England

[2] Univ Oxford, Dept Chem, Chem Res Lab, 12 Mansfield Rd, Oxford OX1 3TA, England

来源：

MOLECULAR ASPECTS OF MEDICINE | 2016年 / 47-48卷

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

Hypoxia; HIF prolyl hydroxylases; Inhibitor; Oxygen sensing; Hypoxia inducible factor (HIF); HIF hydroxylases; HYPOXIA-INDUCIBLE-FACTOR; FACTOR-PROLYL-HYDROXYLASE; ANKYRIN REPEAT DOMAIN; TUMOR-SUPPRESSOR PROTEIN; FACTOR-I; STRUCTURAL BASIS; ASPARAGINYL HYDROXYLATION; FACTOR FIH; MYOCARDIAL-INFARCTION; PROLINE HYDROXYLATION;

D O I：

10.1016/j.mam.2016.01.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2016 Published by Elsevier Ltd.

引用

页码：54 / 75

页数：22

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