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