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

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 and Alessio Ciulli ()
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Julianty Frost: School of Life Sciences, University of Dundee
Carles Galdeano: School of Life Sciences, University of Dundee
Pedro Soares: School of Life Sciences, University of Dundee
Morgan S. Gadd: School of Life Sciences, University of Dundee
Katarzyna M. Grzes: School of Life Sciences, University of Dundee
Lucy Ellis: School of Life Sciences, University of Dundee
Ola Epemolu: School of Life Sciences, University of Dundee
Satoko Shimamura: Cellzome GmbH
Marcus Bantscheff: Cellzome GmbH
Paola Grandi: Cellzome GmbH
Kevin D. Read: School of Life Sciences, University of Dundee
Doreen A. Cantrell: School of Life Sciences, University of Dundee
Sonia Rocha: Center for Gene Regulation and Expression, School of Life Sciences, University of Dundee
Alessio Ciulli: School of Life Sciences, University of Dundee

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13312

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