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Development of inhibitors of the PAS-B domain of the HIF-2? 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-2?-ARNT heterodimerization by binding an internal cavity of the HIF-2? 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-2?-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

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

Rogers Jamie L JL Bayeh Liela L Scheuermann Thomas H TH Longgood Jamie J Key Jason J Naidoo Jacinth J Melito Lisa L Shokri Cameron C Frantz Doug E DE Bruick Richard K RK Gardner Kevin H KH MacMillan John B JB Tambar Uttam K UK

Journal of medicinal chemistry 20130218 4

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 require ...[more]

PMID: 23363003

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