期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/ncomms13312
关键词
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资金
- European Research Council [ERC-2012-StG-311460]
- UK Biotechnology and Biological Sciences Research Council BBSR [BB/G023123/2]
- European Commission [PIEF-GA-2012-328030]
- Wellcome Trust [102398/Z/13/Z, 100476/Z/12/Z, 094090/Z/10/Z]
- Fundacao para a Ciencia e Tecnologia FCT [SFRH/BD/101598/2014]
- Cancer Research UK Senior fellowship [C99667/A12918]
- Wellcome Trust strategic award [097945/B/11/Z]
- BBSRC [BB/G023123/2] Funding Source: UKRI
- Wellcome Trust [102398/Z/13/Z] Funding Source: Wellcome Trust
- Biotechnology and Biological Sciences Research Council [BB/G023123/2] Funding Source: researchfish
- Cancer Research UK [12918] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [SFRH/BD/101598/2014] Funding Source: FCT
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-alpha and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-alpha protein-protein interaction downstream of HIF-alpha 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-alpha 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.
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