Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 94, Issue -, Pages 509-516Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.06.006
Keywords
Hypoxia; HIF; p300/CBP; Zinc ejection; Electrophile; Quinone
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Funding
- Cancer Research UK
- Wellcome Trust
- University of Oxford
- Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD, USA
- British Heart Foundation [PG/12/33/29546] Funding Source: researchfish
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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 alpha 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 alpha and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds. (C) 2014 Elsevier Masson SAS. All rights reserved.
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