title: Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities.
abstract: E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Dow Street, Dundee, DD1 5EH, Scotland, U.K.
authors.forename: Carles
authors.initials: C
authors.lastname: Galdeano
authors.forename: Morgan S
authors.initials: MS
authors.lastname: Gadd
authors.forename: Pedro
authors.initials: P
authors.lastname: Soares
authors.forename: Salvatore
authors.initials: S
authors.lastname: Scaffidi
authors.forename: Inge
authors.initials: I
authors.lastname: Van Molle
authors.forename: Ipek
authors.initials: I
authors.lastname: Birced
authors.forename: Sarah
authors.initials: S
authors.lastname: Hewitt
authors.forename: David M
authors.initials: DM
authors.lastname: Dias
authors.forename: Alessio
authors.initials: A
authors.lastname: Ciulli
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D054852:Small Molecule Libraries; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human