The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.
Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition
Open accessAbstract
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.
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Metadata
- Authors
- Frost, J., Galdeano, C., Soares, P., Gadd, M. S., Grzes, K. M., Ellis, L., Epemolu, O., Shimamura, S., Bantscheff, M., Grandi, P., Read, K. D., Cantrell, D. A., Rocha, S., & Ciulli, A.
- Venue
- Nature Communications
- Published
- 2016-11-04
- Volume
- 7
- Issue
- 1
- Pages
- 13312-13312
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2546637348
- Cited by
- 239
- References
- 24
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- gold
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- Frost, J., Galdeano, C., Soares, P., Gadd, M. S., Grzes, K. M., Ellis, L., Epemolu, O., Shimamura, S., Bantscheff, M., Grandi, P., Read, K. D., Cantrell, D. A., Rocha, S., & Ciulli, A. (2016). Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. Nature Communications. https://doi.org/10.1038/ncomms13312
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