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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 signaling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signaling.
Original language | English |
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Article number | 13312 |
Pages (from-to) | 1-12 |
Number of pages | 12 |
Journal | Nature Communications |
Volume | 7 |
DOIs | |
Publication status | Published - 4 Nov 2016 |
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Dive into the research topics of 'Potent and selective chemical probe of hypoxic signaling downstream of HIF-α hydroxylation via VHL inhibition'. Together they form a unique fingerprint.Projects
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Student Theses
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Small-molecule approaches to interrogate the druggability of the VHL E3 Cullin RING Ubiquitin Ligase
Author: Soares, P., 2018Supervisor: Ciulli, A. (Supervisor)
Student thesis: Doctoral Thesis › Doctor of Philosophy
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Profiles
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Ciulli, Alessio
- Biological Chemistry and Drug Discovery - Professor & Chemical and Structural Biology
Person: Academic