Identification of Small Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor.

Identification of Small Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor.

Chembiochem. 2016 Oct 22;:

Authors: Arsenault PR, Song D, Bergkamp M, Ravaschiere AM, Navalsky BE, Lieberman PM, Lee FS

Abstract
The Prolyl Hydroxylase Domain protein (PHD):Hypoxia Inducible Factor (HIF) pathway is the main pathway by which changes in oxygen concentration are transduced to changes in gene expression. In mammals, there are three PHD paralogues, and PHD2 has emerged as a particularly critical one for regulating HIF target genes such as ERYTHROPOIETIN (EPO), which controls red cell mass and hematocrit. PHD2 is distinctive among the three PHDs in that it contains an N-terminal MYND type zinc finger. We have proposed that this zinc finger binds a Pro-Xaa-Leu-Glu (PXLE) motif found in proteins of the HSP90 pathway to facilitate HIF-α hydroxylation. Targeting it may provide a means of specifically inhibiting this PHD isoform. Here, we screened a library of chemical compounds for their capacity to inhibit the zinc finger of PHD2. We identified compounds that, in vitro, can inhibit PHD2 binding to a PXLE-containing peptide and induce activation of HIF. Injection of one of these compounds into mice induces an increase in hematocrit. This study offers proof of principle that inhibition of the zinc finger of PHD2 can provide a means of selectively targeting PHD2 to activate the HIF pathway.

PMID: 27770548 [PubMed - as supplied by publisher]

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