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Inhibition of the HIF1a-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II)

Inhibition of the HIF1a-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II)
Inhibition of the HIF1a-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II)
Protein–protein interactions between the hypoxia inducible factor (HIF) and the transcriptional coactivators p300/CBP are potential cancer targets due to their role in the hypoxic response. A natural product based screen led to the identification of indandione and benzoquinone derivatives that reduce the tight interaction between a HIF-1? fragment and the CH1 domain of p300. The indandione derivatives were shown to fragment to give ninhydrin, which was identified as the active species. Both the naphthoquinones and ninhydrin were observed to induce Zn(II) ejection from p300 and the catalytic domain of the histone demethylase KDM4A. Together with previous reports on the effects of related compounds on HIF-1? and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds.
0223-5234
509-516
Jayatunga, Madura K.P.
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Thompson, Sam
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McKee, Tawnya C.
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Chan, Mun Chiang
91ab0801-a4dd-4ed4-a643-4d744892a228
Reece, Kelie M.
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Hardy, Adam P.
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Sekirnik, Rok
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Seden, Peter T.
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Cook, Kristina M.
a619cccf-e22b-49ff-880b-e1fc2eb50736
McMahon, James B.
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Figg, William D.
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Schofield, Christopher J.
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Hamilton, Andrew D.
048a6c75-91bf-4555-ab12-ce885eee65dd
Jayatunga, Madura K.P.
a30f1efb-bf44-4a9b-b8d0-4b34e7575313
Thompson, Sam
99b7e34e-fe24-401c-b7b0-64e56cbbbcb1
McKee, Tawnya C.
d089b30e-6c45-4673-b76e-5c59dfd2038e
Chan, Mun Chiang
91ab0801-a4dd-4ed4-a643-4d744892a228
Reece, Kelie M.
391266ce-d7e8-4b94-810f-968c9586eb07
Hardy, Adam P.
aedb9cda-fa68-4211-85e7-a9ce3d6b4420
Sekirnik, Rok
1c971c54-a199-4140-8d31-015efba7f0bb
Seden, Peter T.
4dd1082b-132c-4199-98f4-278b1aa06cb4
Cook, Kristina M.
a619cccf-e22b-49ff-880b-e1fc2eb50736
McMahon, James B.
cf2d7c36-37a5-417d-a2b7-4455078a16e4
Figg, William D.
b6d65fc3-2743-434e-a2d4-9f71c0d1f45e
Schofield, Christopher J.
e6290859-8eda-4bdc-9dfd-d4d682135027
Hamilton, Andrew D.
048a6c75-91bf-4555-ab12-ce885eee65dd

Jayatunga, Madura K.P., Thompson, Sam, McKee, Tawnya C., Chan, Mun Chiang, Reece, Kelie M., Hardy, Adam P., Sekirnik, Rok, Seden, Peter T., Cook, Kristina M., McMahon, James B., Figg, William D., Schofield, Christopher J. and Hamilton, Andrew D. (2015) Inhibition of the HIF1a-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II). European Journal of Medicinal Chemistry, 94, 509-516. (doi:10.1016/j.ejmech.2014.06.006).

Record type: Article

Abstract

Protein–protein interactions between the hypoxia inducible factor (HIF) and the transcriptional coactivators p300/CBP are potential cancer targets due to their role in the hypoxic response. A natural product based screen led to the identification of indandione and benzoquinone derivatives that reduce the tight interaction between a HIF-1? fragment and the CH1 domain of p300. The indandione derivatives were shown to fragment to give ninhydrin, which was identified as the active species. Both the naphthoquinones and ninhydrin were observed to induce Zn(II) ejection from p300 and the catalytic domain of the histone demethylase KDM4A. Together with previous reports on the effects of related compounds on HIF-1? and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds.

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Accepted/In Press date: 3 June 2014
e-pub ahead of print date: 27 June 2014
Published date: 13 April 2015
Organisations: Chemistry

Identifiers

Local EPrints ID: 403600
URI: http://eprints.soton.ac.uk/id/eprint/403600
ISSN: 0223-5234
PURE UUID: 4ab02b86-7126-45d2-9ab7-e6049b8c2dd5
ORCID for Sam Thompson: ORCID iD orcid.org/0000-0001-6267-5693

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Date deposited: 07 Dec 2016 11:12
Last modified: 17 Dec 2019 01:32

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Contributors

Author: Madura K.P. Jayatunga
Author: Sam Thompson ORCID iD
Author: Tawnya C. McKee
Author: Mun Chiang Chan
Author: Kelie M. Reece
Author: Adam P. Hardy
Author: Rok Sekirnik
Author: Peter T. Seden
Author: Kristina M. Cook
Author: James B. McMahon
Author: William D. Figg
Author: Christopher J. Schofield
Author: Andrew D. Hamilton

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