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



Frost, Julianty ORCID: 0000-0001-8209-2575, Galdeano, Carles, Soares, Pedro, Gadd, Morgan S, Grzes, Katarzyna M, Ellis, Lucy, Epemolu, Ola, Shimamura, Satoko, Bantscheff, Marcus, Grandi, Paola
et al (show 4 more authors) (2016) Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. Nature communications, 7.

Access the full-text of this item by clicking on the Open Access link.

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.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 10 Jan 2018 09:53
Last Modified: 09 Jun 2021 19:11
DOI: 10.1038/ncomms13312
Open Access URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC50971...
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3015770