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

被引：113

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. ^{[1
]}

MacMillan, John B.

Tambar, Uttam K.

机构：

[1] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 04期

基金：

美国国家卫生研究院;

关键词：

HYPOXIA-INDUCIBLE FACTOR; ARYL-HYDROCARBON RECEPTOR; LIGAND-BINDING; CANCER-THERAPY; HIF-1; INHIBITORS; FACTOR-I; PROGRESSION;

D O I：

10.1021/jm301847z

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

收藏

页码：1739 / 1747

页数：9

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