Abstract
As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.
Highlights
In metazoans, the α/β heterodimeric hypoxia-inducible factor (HIF) complex activates the expression of hundreds of target genes in response to hypoxia, including those involved in cell growth, apoptosis, energy metabolism and angiogenesis [1]
Given that the PHDs are part of the human 2OG-dependent oxygenase family which comprises ~60 members, we investigated the selectivity of 1 and IOX4 by screening against a panel of human 2OG oxygenases, including the human Jumonji C (JmjC)-domain containing histone demethylases (KDMs), γ-butyrobetaine hydroxylase (BBOX) and the fat mass and obesity associated protein (FTO)
The combined kinetic and biophysical analyses reveal that IOX4 compete with 2OG for binding to PHD2; the triazole rings of the inhibitors bind in the pocket occupied by the CH2CH2COOH side chain of 2OG
Summary
The α/β heterodimeric hypoxia-inducible factor (HIF) complex activates the expression of hundreds of target genes in response to hypoxia, including those involved in cell growth, apoptosis, energy metabolism and angiogenesis [1]. Potent and Selective HIF Prolyl-Hydroxylase Inhibitors inhibiting HIF (FIH), a modification which blocks the recruitment of the transcriptional coactivators CBP/p300 to HIFα, so causing reduced HIF transcriptional activity [7,8]. The activities of both the PHDs and FIH are suppressed by limiting oxygen, resulting in HIFα stabilization and activation of the HIF system. Various compounds have been reported as PHD inhibitors in the academic and patent literature [10,11,12] Most of these compounds likely bind to the active site iron and compete with 2-oxoglutarate (2OG). A set of tricyclic PHD inhibitor with linked pyridine-carboxylate, doi:10.1371/journal.pone.0132004.g001
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