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Selective Small Molecule Probes for the Hypoxia Inducible Factor (HIF) Prolyl Hydroxylases

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journal contribution
posted on 19.07.2013, 00:00 by Rasheduzzaman Chowdhury, José 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
The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-α 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.