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

  • J Med Chem. 2013 Feb 28;56(4):1739-47. doi: 10.1021/jm301847z.
Jamie L Rogers  1 ,  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
Affiliations
  • 1. Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
PMID: 23363003 DOI: 10.1021/jm301847z
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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