Abstract
Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in a variety of pathophysiological settings, including cancer. We describe the first detailed structure-activity relationship study of small molecules designed to inhibit HIF-2α-ARNT heterodimerization by binding an internal cavity of the HIF-2α PAS-B domain. Through a series of biophysical characterizations of inhibitor-protein interactions (NMR and X-ray crystallography), we have established the structural requirements for artificial inhibitors of the HIF-2α-ARNT PAS-B interaction. These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aryl Hydrocarbon Receptor Nuclear Translocator / chemistry
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Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors*
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Basic Helix-Loop-Helix Transcription Factors / chemistry
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Crystallography, X-Ray
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High-Throughput Screening Assays
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Humans
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Structure
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Mutation
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Oxadiazoles / chemical synthesis
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Oxadiazoles / chemistry
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Protein Binding
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Protein Multimerization
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Protein Structure, Tertiary
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Small Molecule Libraries / chemistry
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Structure-Activity Relationship
Substances
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ARNT protein, human
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Basic Helix-Loop-Helix Transcription Factors
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Oxadiazoles
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Small Molecule Libraries
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Aryl Hydrocarbon Receptor Nuclear Translocator
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endothelial PAS domain-containing protein 1