title: Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction.
abstract: E3 ubiquitin ligases, which bind protein targets, leading to their ubiquitination and subsequent degradation, are attractive drug targets due to their exquisite substrate specificity. However, the development of small-molecule inhibitors has proven extraordinarily challenging as modulation of E3 ligase activities requires the targeting of protein-protein interactions. Using rational design, we have generated the first small molecule targeting the von Hippel-Lindau protein (VHL), the substrate recognition subunit of an E3 ligase, and an important target in cancer, chronic anemia, and ischemia. We have also obtained the crystal structure of VHL bound to our most potent inhibitor, confirming that the compound mimics the binding mode of the transcription factor HIF-1α, a substrate of VHL. These results have the potential to guide future development of improved lead compounds as therapeutics for the treatment of chronic anemia and ischemia.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Buckley
authors.forename: Inge
authors.initials: I
authors.lastname: Van Molle
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gareiss
authors.forename: Hyun Seop
authors.initials: HS
authors.lastname: Tae
authors.forename: Julien
authors.initials: J
authors.lastname: Michel
authors.forename: Devin J
authors.initials: DJ
authors.lastname: Noblin
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.forename: Alessio
authors.initials: A
authors.lastname: Ciulli
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D054852:Small Molecule Libraries; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects* / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000187:drug effects* / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D054852:Small Molecule Libraries; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human