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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.

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  • Carles Galdeano
  • Morgan Stuart Gadd
  • Pedro Soares
  • Salvatore Scaffidi
  • Inge van Molle
  • Ipek Birced
  • Sarah Hewitt
  • David M Dias
  • Alessio Ciulli
<mark>Journal publication date</mark>23/10/2014
<mark>Journal</mark>Journal of Medicinal Chemistry
Issue number20
Number of pages7
Pages (from-to)8657-8663
Publication StatusPublished
Early online date6/10/14
<mark>Original language</mark>English


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.