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Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials
Chemical Science ( IF 7.6 ) Pub Date : 2017-09-11 00:00:00 , DOI: 10.1039/c7sc02103h
Tzu-Lan Yeh 1, 2, 3, 4, 5 , Thomas M. Leissing 1, 2, 3, 4, 5 , Martine I. Abboud 1, 2, 3, 4, 5 , Cyrille C. Thinnes 1, 2, 3, 4, 5 , Onur Atasoylu 1, 2, 3, 4, 5 , James P. Holt-Martyn 1, 2, 3, 4, 5 , Dong Zhang 1, 2, 3, 4, 5 , Anthony Tumber 1, 2, 3, 4, 5 , Kerstin Lippl 1, 2, 3, 4, 5 , Christopher T. Lohans 1, 2, 3, 4, 5 , Ivanhoe K. H. Leung 1, 2, 3, 4, 5 , Helen Morcrette 6, 7, 8, 9, 10 , Ian J. Clifton 1, 2, 3, 4, 5 , Timothy D. W. Claridge 1, 2, 3, 4, 5 , Akane Kawamura 1, 2, 3, 4, 5 , Emily Flashman 1, 2, 3, 4, 5 , Xin Lu 3, 5, 11, 12, 13 , Peter J. Ratcliffe 3, 5, 14, 15, 16 , Rasheduzzaman Chowdhury 1, 2, 3, 4, 5 , Christopher W. Pugh 3, 5, 14, 15, 16 , Christopher J. Schofield 1, 2, 3, 4, 5
Affiliation  

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.

中文翻译:

HIF脯氨酰羟化酶抑制剂的分子和细胞机制在临床试验中

抑制人类2-氧戊二酸酯(2OG)依赖性的缺氧诱导因子(HIF)脯氨酰羟化酶(人类PHD1-3)会导致HIF上调,从而促进红细胞生成,因此具有治疗价值。我们描述了细胞,生物物理和生化研究,比较了目前在贫血治疗的临床试验中使用的四种PHD抑制剂,这些抑制剂描述了它们的作用机理,针对分离的酶和细胞的效力以及选择性其他人类2OG加氧酶亚家族的代表。“临床” PHD抑制剂是PHD催化的HIF-α氧依赖性降解域(ODD)的羟基化的有效抑制剂,对大多数但不是全部代表其他人类2OG依赖性双加氧酶亚家族具有选择性。晶体学和NMR研究提供了对抑制剂不同活性位点结合方式的见解。基于细胞的结果表明,这些抑制剂对HIF靶基因的上调具有相似的作用,但是在其作用动力学以及N和C端ODD羟基化抑制程度方面有所不同。后者的差异与生物物理观察结果相关。
更新日期:2017-10-23
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