Abstract
Small molecules inhibiting hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are the focus of drug development efforts directed toward the treatment of ischemia and metabolic imbalance. A cell-based reporter produced by fusing HIF-1 alpha oxygen degradable domain (ODD) to luciferase was shown to work as a capture assay monitoring stability of the overexpressed luciferase-labeled HIF PHD substrate under conditions more physiological than in vitro test tubes. High throughput screening identified novel catechol and oxyquinoline pharmacophores with a "branching motif" immediately adjacent to a Fe-binding motif that fits selectively into the HIF PHD active site in in silico models. In accord with their structure-activity relationship in the primary screen, the best "hits" stabilize HIF1 alpha, upregulate known HIF target genes in a human neuronal line, and exert neuroprotective effects in established model of oxidative stress in cortical neurons.
(c) 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Catechols / chemistry
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Catechols / pharmacology*
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Cell Line, Tumor
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Dioxygenases / antagonists & inhibitors*
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Dioxygenases / chemistry
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Dioxygenases / metabolism
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High-Throughput Screening Assays / methods*
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Humans
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Hydrazines / chemistry
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Hydrazines / pharmacology
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Hypoxia / drug therapy*
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Hypoxia-Inducible Factor 1 / metabolism
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Models, Molecular
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism
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Oxidative Stress / drug effects
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Oxyquinoline / chemistry
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Oxyquinoline / pharmacology*
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Procollagen-Proline Dioxygenase
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Structure-Activity Relationship
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Thiadiazoles / chemistry
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Thiadiazoles / pharmacology
Substances
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Catechols
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Hydrazines
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Hypoxia-Inducible Factor 1
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Neuroprotective Agents
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Nuclear Proteins
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Thiadiazoles
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Oxyquinoline
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Dioxygenases
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Procollagen-Proline Dioxygenase
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EGLN2 protein, human
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Hypoxia-Inducible Factor-Proline Dioxygenases
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catechol