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. Epub 2014 Oct 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ligands
  • Small Molecule Libraries
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human

Associated data

  • PDB/4W9C
  • PDB/4W9D
  • PDB/4W9E
  • PDB/4W9F
  • PDB/4W9G
  • PDB/4W9H
  • PDB/4W9I
  • PDB/4W9J
  • PDB/4W9K
  • PDB/4W9L