|
D. M. Hushpulian, S. V. Nikulin, T. A. Chubar, A. Yu. Khristichenko, A. A. Poloznikov, I. G. Gazaryan
Fast responding genes to HIF prolyl
hydroxylase inhibitors
Abstract
The attempts to elucidate the mechanism of
hypoxic activation of erythropoietin synthesis lead to the discovery of hypoxia
inducible factor (HIF) and its stability regulation via HIF prolyl hydroxylase,
iron and α-ketoglutarate dependent dioxygenase.
Enzyme inhibitors mimic the action of hypoxia, however, are far more specific.
Comparative transcriptomic microanalysis of various types of the enzyme
inhibitors versus hypoxia at short incubation times demonstrates high potency
of inhibitors and points to the primary targets of HIF transcription factor.
The power of inhibitors evaluated in the transcriptomic analysis matches the
ranking of enzyme inhibitors based on the values of their half-activation
constants in HIF1 ODD-luc reporter assay. Neuradapt is 15-20 times more potent
than roxadustat, and in addition, it is much more specific for the target
enzyme than roxadustat and dimethyl oxalylglycine, which are likely acting on
other enzymes of the same family.
Key words: hypoxia, transcriptome,
roxadustat, neuradapt, dimethyl oxalylglycine, gene expression.
Copyright (C) Chemistry Dept., Moscow State University, 2002
|
|
