Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials
Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials
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DOI：
10.1039/c7sc02103h
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发表时间：
2017-11-01
期刊：
影响因子：
8.4
通讯作者：
Schofield, Christopher J.
中科院分区：
文献类型：
--
作者：
Yeh, Tzu-Lan;Leissing, Thomas M.;Schofield, Christopher J.
抑制人2-氧戊二酸（2OG）依赖的缺氧诱导因子（HIF）脯氨酸羟化酶（人PHD1-3）导致HIF上调，从而促进红细胞生成，因此具有治疗意义。我们描述了目前在贫血治疗临床试验中比较四种PHD抑制剂的细胞，生物物理和生化研究，描述了它们的作用机制，对分离酶和细胞的效力，以及与其他人类2g加氧酶亚家族代表的选择性。“临床”PHD抑制剂是PHD催化的HIF-a氧依赖降解域（ODDs）羟基化的有效抑制剂，并且对大多数（但不是全部）其他人类2g依赖双加氧酶亚家族的代表具有选择性。晶体学和核磁共振研究提供了抑制剂的不同活性位点结合模式的见解。基于细胞的结果显示，抑制剂对HIF靶基因的上调具有相似的作用，但其作用动力学和对n和c端ODDs羟基化的抑制程度不同；后一种差异与生物物理观察结果有关。
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-a 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.