Development of Inhibitors of the PAS-B Domain of the HIF-2 alpha Transcription Factor

作者：Rogers Jamie L; Bayeh Liela; Scheuermann Thomas H; Longgood Jamie; Key Jason; Naidoo Jacinth; Melito Lisa; Shokri Cameron; Frantz Doug E; Bruick Richard K; Gardner Kevin H^*; MacMillan John B; Tambar Uttam K

来源：Journal of Medicinal Chemistry, 2013, 56(4): 1739-1747.

DOI：10.1021/jm301847z

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 alpha-ARNT heterodimerization by binding an internal cavity of the HIF-2 alpha 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 alpha-ARNT PAS-B interaction. These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action.

• 出版日期2013-2-28