Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor

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

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1739-1747
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number4
StatePublished - Feb 28 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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