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Issue 9, 2013
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Azole derivatives as novel non-iron-chelating inhibitors of prolyl hydroxylase 3 for HIF-1 activation

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Abstract

Prolyl hydroxylase 3 (PHD3) controls hypoxia-inducible factor-1 (HIF-1) degradation by oxygen dependent hydroxylation. PHD3 inhibitors are potential targets for HIF-1α activation, thereby treating a number of HIF-related diseases. We herein rationally designed a novel scaffold for PHD3 inactivation under the guidance of enzyme–ligand docking simulation studies. The potent inhibitors were able to non-covalently bind to the active site of PHD3, and to stabilize the core domain resisting to trypsin proteolysis. The conformational changes of the protein occurred concomitant with inhibitor binding, which thus deactivated the enzyme. The up-regulated levels of HIF-1α protein and downstream genes (glucose transporter-1 (GLUT-1) and vascular endothelial growth factor (VEGF)) suggest that the PHD inhibitors manage to mimic the cellular signalling effects of hypoxia. Interestingly, unlike available PHD inhibitors, the iron-chelating motif is not found in all azole compounds, among which we identified a unique compound 1-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-1H-benzo[d][1,2,3]triazole (BEBT) as the most effective inhibitor. BEBT binds to the enzyme with the lowest predicted binding energy, and activates HIF activity most significantly in cellular systems. This novel non-iron-chelating inhibitor offers a new target for the drug design towards hypoxia-related diseases therapy with possibly minimized iron-relating side effects.

Graphical abstract: Azole derivatives as novel non-iron-chelating inhibitors of prolyl hydroxylase 3 for HIF-1 activation

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Publication details

The article was received on 18 Apr 2013, accepted on 01 Jul 2013 and first published on 01 Jul 2013


Article type: Concise Article
DOI: 10.1039/C3MD00117B
Med. Chem. Commun., 2013,4, 1222-1230

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    Azole derivatives as novel non-iron-chelating inhibitors of prolyl hydroxylase 3 for HIF-1 activation

    J. Cao, X. Ma, X. Wang, X. Wang, Z. Zhang, Z. Geng and Z. Wang, Med. Chem. Commun., 2013, 4, 1222
    DOI: 10.1039/C3MD00117B

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