Home > Research > Publications & Outputs > Structure-guided design and optimization of sma...

Links

Text available via DOI:

View graph of relations

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.

Research output: Contribution to journalJournal article

Published
  • Carles Galdeano
  • Morgan Stuart Gadd
  • Pedro Soares
  • Salvatore Scaffidi
  • Inge van Molle
  • Ipek Birced
  • Sarah Hewitt
  • David M Dias
  • Alessio Ciulli
Close
<mark>Journal publication date</mark>23/10/2014
<mark>Journal</mark>Journal of Medicinal Chemistry
Issue number20
Volume57
Number of pages7
Pages (from-to)8657-8663
Publication statusPublished
Early online date6/10/14
Original languageEnglish

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.