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 C.hiang 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)509-516
Number of pages8
JournalEuropean journal of medicinal chemistry
Volume94
DOIs
StatePublished - 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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    Jayatunga, M. K. P., Thompson, S., McKee, T. C., Chan, M. C. H., 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