Selective Small Molecule Probes for the Hypoxia Inducible Factor (HIF) Prolyl Hydroxylases
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- 作者：Rasheduzzaman Chowdhury ; Jos茅 Ignacio Candela-Lena ; Mun Chiang Chan ; David Jeremy Greenald ; Kar Kheng Yeoh ; Ya-Min Tian ; Michael A. McDonough ; Anthony Tumber ; Nathan R. Rose ; Ana Conejo-Garcia ; Marina Demetriades ; Sinnakaruppan Mathavan ; Akane Kawamura ; Myung Kyu Lee ; Freek van Eeden ; Christopher W. Pugh ; Peter J. Ratcliffe ; Christopher J. Schofield
- 刊名：ACS Chemical Biology
- 出版年：2013
- 出版时间：July 19, 2013
- 年：2013
- 卷：8
- 期：7
- 页码：1488-1496
- 全文大小：693K
- 年卷期：v.8,no.7(July 19, 2013)
- ISSN：1554-8937
文摘
The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-伪 isoforms are regulated in an oxygen-dependent manner by the activity of the HIF prolyl-hydroxylases (PHD or EGLN enzymes), which are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, we describe biochemical, crystallographic, cellular profiling, and animal studies on PHD inhibitors including selectivity studies using a representative set of human 2OG oxygenases. We identify suitable probe compounds for use in studies on the functional effects of PHD inhibition in cells and in animals.