title: Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2.
abstract: Hypoxia inducible factor (HIF) transcription factors reside at the center of signaling pathways used by mammalian cells to sense and respond to low oxygen levels. While essential to maintain oxygen homeostasis, misregulation of HIF protein activity correlates with tumor development and metastasis. To provide artificial routes to target misregulated HIF activity, we identified small molecule antagonists of the HIF-2 transcription factor that bind an internal cavity within the C-terminal PAS domain of the HIF-2α subunit. Here we describe a new class of chiral small molecule ligands that provide the highest affinity binding, the most effective, isoform-selective inhibition of HIF-2 in cells, and trigger the largest protein conformation changes reported to date. The current results further illuminate the molecular mechanism of HIF-2 antagonism and suggest additional routes to develop higher affinity and potency HIF-2 antagonists.
authors.affiliation: †Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Scheuermann
authors.affiliation: ‡Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stroud
authors.affiliation: ‡Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Sleet
authors.affiliation: ‡Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Liela
authors.initials: L
authors.lastname: Bayeh
authors.affiliation: ‡Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Cameron
authors.initials: C
authors.lastname: Shokri
authors.affiliation: ‡Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Hanzhi
authors.initials: H
authors.lastname: Wang
authors.affiliation: ‡Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Caldwell
authors.affiliation: ‡Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Jamie
authors.initials: J
authors.lastname: Longgood
authors.affiliation: ‡Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: John B
authors.initials: JB
authors.lastname: MacMillan
authors.affiliation: ‡Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Bruick
authors.affiliation: †Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.|§Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York 10031, United States.|∥Department of Chemistry and Biochemistry, City College of New York, New York, New York 10031, United States.
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Gardner
authors.affiliation: ‡Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Uttam K
authors.initials: UK
authors.lastname: Tambar
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D020033:Protein Isoforms / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D020033:Protein Isoforms; D000099162:Endothelial PAS Domain-Containing Protein 1