Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II)

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

doi:10.1016/j.ejmech.2014.06.006

Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II)

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

Chemistry

Research output: Contribution to journal › Article › peer-review

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-1α 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-1α and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds.

Original language	English (US)
Pages (from-to)	509-516
Number of pages	8
Journal	European journal of medicinal chemistry
Volume	94
DOIs	https://doi.org/10.1016/j.ejmech.2014.06.006
State	Published - Apr 13 2015

Keywords

Electrophile
HIF
Hypoxia
Quinone
Zinc ejection
p300/CBP

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2014.06.006

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Jayatunga, M. K. P., Thompson, S., McKee, T. C., Chan, M. C., Reece, K. M., Hardy, A. P., Sekirnik, R., Seden, P. T., Cook, K. M., McMahon, J. B., Figg, W. D., Schofield, C. J., & Hamilton, A. D. (2015). Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II). European journal of medicinal chemistry, 94, 509-516. https://doi.org/10.1016/j.ejmech.2014.06.006

Jayatunga, MKP, Thompson, S, McKee, TC, Chan, MC, Reece, KM, Hardy, AP, Sekirnik, R, Seden, PT, Cook, KM, McMahon, JB, Figg, WD, Schofield, CJ & Hamilton, AD 2015, 'Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II)', European journal of medicinal chemistry, vol. 94, pp. 509-516. https://doi.org/10.1016/j.ejmech.2014.06.006

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title = "Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II)",

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-1α 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-1α and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds.",

keywords = "Electrophile, HIF, Hypoxia, Quinone, Zinc ejection, p300/CBP",

author = "Jayatunga, {Madura K.P.} and Sam Thompson and McKee, {Tawnya C.} and Chan, {Mun Chiang} and Reece, {Kelie M.} and Hardy, {Adam P.} and Rok Sekirnik and Seden, {Peter T.} and Cook, {Kristina M.} and McMahon, {James B.} and Figg, {William D.} and Schofield, {Christopher J.} and Hamilton, {Andrew D.}",

note = "Funding Information: We thank Cancer Research UK (MKPJ) , the Wellcome Trust , and the University of Oxford (ST) for funding. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD, USA. Publisher Copyright: {\textcopyright} 2014 Elsevier Masson SAS",

year = "2015",

month = apr,

day = "13",

doi = "10.1016/j.ejmech.2014.06.006",

language = "English (US)",

volume = "94",

pages = "509--516",

journal = "European journal of medicinal chemistry",

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T1 - Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II)

AU - Jayatunga, Madura K.P.

AU - Thompson, Sam

AU - McKee, Tawnya C.

AU - Chan, Mun Chiang

AU - Reece, Kelie M.

AU - Hardy, Adam P.

AU - Sekirnik, Rok

AU - Seden, Peter T.

AU - Cook, Kristina M.

AU - McMahon, James B.

AU - Figg, William D.

AU - Schofield, Christopher J.

AU - Hamilton, Andrew D.

N1 - Funding Information: We thank Cancer Research UK (MKPJ) , the Wellcome Trust , and the University of Oxford (ST) for funding. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD, USA. Publisher Copyright: © 2014 Elsevier Masson SAS

PY - 2015/4/13

Y1 - 2015/4/13

N2 - 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-1α 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-1α and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds.

AB - 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-1α 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-1α and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds.

KW - Electrophile

KW - HIF

KW - Hypoxia

KW - Quinone

KW - Zinc ejection

KW - p300/CBP

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JF - European journal of medicinal chemistry

ER -

Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II)

Abstract

Keywords

ASJC Scopus subject areas

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