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Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition

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  • Julianty Frost
  • Carles Galdeano
  • Pedro Soares
  • Morgan S Gadd
  • Katarzyna M Grzes
  • Lucy Ellis
  • Ola Epemolu
  • Satoko Shimamura
  • Marcus Bantscheff
  • Paola Grandi
  • Kevin D Read
  • Doreen A Cantrell
  • Sonia Rocha
  • Alessio Ciulli
Article number13312
<mark>Journal publication date</mark>4/11/2016
<mark>Journal</mark>Nature Communications
Number of pages12
Publication StatusPublished
<mark>Original language</mark>English


Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.