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

Carles Galdeano , Morgan S. Gadd, Pedro Soares, Salvatore Scaffidi, Inge Van Molle, Ipek Birced, Sarah Hewitt, David M. Dias, Alessio Ciulli (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    122 Citations (Scopus)
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    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.

    Original languageEnglish
    Pages (from-to)8657-8663
    Number of pages7
    JournalJournal of Medicinal Chemistry
    Volume57
    Issue number20
    DOIs
    Publication statusPublished - 23 Oct 2014

    Keywords

    • Crystallography, X-Ray
    • Humans
    • Hypoxia-Inducible Factor 1, alpha Subunit
    • Ligands
    • Models, Molecular
    • Molecular Targeted Therapy
    • Protein Binding
    • Small Molecule Libraries
    • Structure-Activity Relationship
    • Von Hippel-Lindau Tumor Suppressor Protein

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