Time-Dependent Inhibition of PHD2.

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Time-Dependent Inhibition of PHD2.

Biosci Rep. 2017 Jun 07;:

Authors: Tcholakov I, Grimshaw CE, Shi L, Kiryanov A, Murphy ST, Larson CJ, Plonowski A, Ermolieff J

Abstract
Prolyl Hydroxylases (PHDs) down-regulate the level of hypoxia-inducible factors (HIFs) by hydroxylating key proline residues which triggers the degradation of the protein and affect the cell and its ability to respond to hypoxic stress. Several small molecule PHD inhibitors are now in various preclinical and clinical stages for the treatment of anemia. This study provides a detail kinetic analysis for some of these inhibitors. The data generated in this study suggest that these compounds are reversible and compete directly with the co-substrate, 2-oxoglutarate (2-OG) for binding at the enzyme active site. Most of these compounds are pan PHD inhibitors and exhibit a time-dependent inhibition (TDI) mechanism due to an extremely slow dissociation rate constant, koff, and a long residence time.

PMID: 28592559 [PubMed - as supplied by publisher]

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