Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition
Year: 2016
Type: article
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.
Source: Nature Communications
DOI: 10.1038/ncomms13312
Institution: University of Dundee
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,678
Awards: Design of orthogonal molecular probes targeting engineered von-Hippel Lindau (VHL) E3 ubiquitin ligase for the control of intracellular protein levels, A combinatorial approach for enhancing cell transplantation for neurological diseases via simple and scalable chemistries, A Translational Engine for Biomedical Discoveries ., G2467081406, G4160324960, State-of-the-art facilities for structural biology at the University of Dundee., Novel Approaches to Interrogate the Druggability of E3 Cullin RING Ubiquitin Ligases, Investigating the functions of VHL and HIF using small molecules that disrupt the VHL/HIF-1alpha interaction, G7381010196, G7805879211, Wellcome Trust Technology Platform, G7958694352, G808174064
OpenAlex ID: W2546637348