2. Academic Validation
  3. 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

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

  • J Med Chem. 2014 Oct 23;57(20):8657-63. doi: 10.1021/jm5011258.
Carles Galdeano 1,  Morgan S Gadd,  Pedro Soares,  Salvatore Scaffidi,  Inge Van Molle,  Ipek Birced,  Sarah Hewitt,  David M Dias,  Alessio Ciulli
Affiliations

Affiliation

  • 1 Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Dow Street, Dundee, DD1 5EH, Scotland, U.K.
PMID: 25166285 DOI: 10.1021/jm5011258
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.

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