Development of Inhibitors of the PAS-B Domain of the HIF-2α Transcription Factor
Jamie L. Rogers(The University of Texas Southwestern Medical Center), Liela Bayeh(The University of Texas Southwestern Medical Center), Thomas H. Scheuermann(The University of Texas Southwestern Medical Center), Jamie Longgood(The University of Texas Southwestern Medical Center), Jason Key(The University of Texas Southwestern Medical Center), Jacinth Naidoo(The University of Texas Southwestern Medical Center), Lisa Melito(The University of Texas Southwestern Medical Center), Cameron Shokri(The University of Texas Southwestern Medical Center), Doug E. Frantz(The University of Texas Southwestern Medical Center), Richard K. Bruick(Southwestern Medical Center), Kevin H. Gardner(The University of Texas Southwestern Medical Center), John B. MacMillan(The University of Texas Southwestern Medical Center), Uttam K. Tambar(The University of Texas Southwestern Medical Center)
Cited by 136Open Access
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.