Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor.
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.
Mesh Terms:
Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Transcription Factors, Crystallography, X-Ray, High-Throughput Screening Assays, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Structure, Mutation, Oxadiazoles, Protein Binding, Protein Multimerization, Protein Structure, Tertiary, Small Molecule Libraries, Structure-Activity Relationship
Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Transcription Factors, Crystallography, X-Ray, High-Throughput Screening Assays, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Structure, Mutation, Oxadiazoles, Protein Binding, Protein Multimerization, Protein Structure, Tertiary, Small Molecule Libraries, Structure-Activity Relationship
J. Med. Chem.
Date: Feb. 28, 2013
PubMed ID: 23363003
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