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

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

doi:10.1021/jm301847z

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

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

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1739-1747
Number of pages	9
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	4
DOIs	https://doi.org/10.1021/jm301847z
State	Published - Feb 28 2013

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm301847z

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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.",

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AU - Rogers, Jamie L.

AU - Bayeh, Liela

AU - Scheuermann, Thomas H.

AU - Longgood, Jamie

AU - Key, Jason

AU - Naidoo, Jacinth

AU - Melito, Lisa

AU - Shokri, Cameron

AU - Frantz, Doug E.

AU - Bruick, Richard K.

AU - Gardner, Kevin H.

AU - MacMillan, John B.

AU - Tambar, Uttam K.

PY - 2013/2/28

Y1 - 2013/2/28

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AB - 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.

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

Abstract

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