Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor.
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.
Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
Jamie L
JL
Rogers
Liela
L
Bayeh
Thomas H
TH
Scheuermann
Jamie
J
Longgood
Jason
J
Key
Jacinth
J
Naidoo
Lisa
L
Melito
Cameron
C
Shokri
Doug E
DE
Frantz
Richard K
RK
Bruick
Kevin H
KH
Gardner
John B
JB
MacMillan
Uttam K
UK
Tambar
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000737:chemistry; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D018360:Crystallography, X-Ray; D057166:High-Throughput Screening Assays; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry; D013329:Structure-Activity Relationship; D000099162:Endothelial PAS Domain-Containing Protein 1
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D010069:Oxadiazoles; D054852:Small Molecule Libraries; D000099162:Endothelial PAS Domain-Containing Protein 1; C497396:ARNT protein, human