Development of Inhibitors of the PAS-B Domain of the HIF-2α Transcription Factor

Journal of Medicinal Chemistry (Impact Factor: 5.45). 01/2013; 56(4). DOI: 10.1021/jm301847z
Source: PubMed


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.

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