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

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Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. / Frost, Julianty; Galdeano, Carles; Soares, Pedro et al.
In: Nature Communications, Vol. 7, 13312, 04.11.2016.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Frost, J, Galdeano, C, Soares, P, Gadd, MS, Grzes, KM, Ellis, L, Epemolu, O, Shimamura, S, Bantscheff, M, Grandi, P, Read, KD, Cantrell, DA, Rocha, S & Ciulli, A 2016, 'Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition', Nature Communications, vol. 7, 13312. https://doi.org/10.1038/ncomms13312

APA

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, 7, Article 13312. https://doi.org/10.1038/ncomms13312

Vancouver

Frost J, Galdeano C, Soares P, Gadd MS, Grzes KM, Ellis L et al. Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. Nature Communications. 2016 Nov 4;7:13312. doi: 10.1038/ncomms13312

Author

Frost, Julianty ; Galdeano, Carles ; Soares, Pedro et al. / Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. In: Nature Communications. 2016 ; Vol. 7.

Bibtex

@article{92cc8d1ea05d4beb98e8ceaf76839582,
title = "Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition",
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.",
keywords = "Chemical tools, Small molecules, Target validaiton",
author = "Julianty Frost and Carles Galdeano and Pedro Soares and Gadd, {Morgan S} and Grzes, {Katarzyna M} and Lucy Ellis and Ola Epemolu and Satoko Shimamura and Marcus Bantscheff and Paola Grandi and Read, {Kevin D} and Cantrell, {Doreen A} and Sonia Rocha and Alessio Ciulli",
year = "2016",
month = nov,
day = "4",
doi = "10.1038/ncomms13312",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition

AU - Frost, Julianty

AU - Galdeano, Carles

AU - Soares, Pedro

AU - Gadd, Morgan S

AU - Grzes, Katarzyna M

AU - Ellis, Lucy

AU - Epemolu, Ola

AU - Shimamura, Satoko

AU - Bantscheff, Marcus

AU - Grandi, Paola

AU - Read, Kevin D

AU - Cantrell, Doreen A

AU - Rocha, Sonia

AU - Ciulli, Alessio

PY - 2016/11/4

Y1 - 2016/11/4

N2 - 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.

AB - 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.

KW - Chemical tools

KW - Small molecules

KW - Target validaiton

U2 - 10.1038/ncomms13312

DO - 10.1038/ncomms13312

M3 - Journal article

C2 - 27811928

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 13312

ER -