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

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.

SUBMITTER: Rogers JL 

PROVIDER: S-EPMC3676484 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature