Development of Inhibitors of the PAS-B Domain of the HIF-2α Transcription Factor
Journal of Medicinal Chemistry2013Vol. 56(4), pp. 1739–1747
Citations Over TimeTop 10% of 2013 papers
Jamie L. Rogers, Liela Bayeh, Thomas H. Scheuermann, Jamie Longgood, Jason Key, Jacinth Naidoo, Lisa Melito, Cameron Shokri, Doug E. Frantz, Richard K. Bruick, Kevin H. Gardner, John B. MacMillan, Uttam K. Tambar
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.
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