title: Allosteric inhibition of hypoxia inducible factor-2 with small molecules.
abstract: Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in many cancers where they frequently promote the expression of protumorigenic pathways. Though transcription factors are typically considered 'undruggable', the PAS-B domain of the HIF-2α subunit contains a large cavity within its hydrophobic core that offers a unique foothold for small-molecule regulation. Here we identify artificial ligands that bind within this pocket and characterize the resulting structural and functional changes caused by binding. Notably, these ligands antagonize HIF-2 heterodimerization and DNA-binding activity in vitro and in cultured cells, reducing HIF-2 target gene expression. Despite the high sequence identity between HIF-2α and HIF-1α, these ligands are highly selective and do not affect HIF-1 function. These chemical tools establish the molecular basis for selective regulation of HIF-2, providing potential therapeutic opportunities to intervene in HIF-2-driven tumors, such as renal cell carcinomas.
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Thomas H
authors: TH
authors: Scheuermann
authors: Qiming
authors: Q
authors: Li
authors: He-Wen
authors: HW
authors: Ma
authors: Jason
authors: J
authors: Key
authors: Lei
authors: L
authors: Zhang
authors: Rui
authors: R
authors: Chen
authors: Joseph A
authors: JA
authors: Garcia
authors: Jacinth
authors: J
authors: Naidoo
authors: Jamie
authors: J
authors: Longgood
authors: Doug E
authors: DE
authors: Frantz
authors: Uttam K
authors: UK
authors: Tambar
authors: Kevin H
authors: KH
authors: Gardner
authors: Richard K
authors: RK
authors: Bruick
mesh_terms: D000494:Allosteric Regulation; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D008024:Ligands; D009363:Neoplasm Proteins; D054852:Small Molecule Libraries; D000099162:Endothelial PAS Domain-Containing Protein 1