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|Title:||Allosteric cross-talk in chromatin can mediate drug-drug synergy||Authors:||Adhireksan, Zenita
Dyson, Paul J.
Davey, Curtis Alexander
|Issue Date:||2017||Source:||Adhireksan, Z., Palermo, G., Riedel, T., Ma, Z., Muhammad, R., Rothlisberger, U., et al. (2017). Allosteric cross-talk in chromatin can mediate drug-drug synergy. Nature Communications, 8, 14860-.||Series/Report no.:||Nature Communications||Abstract:||Exploitation of drug–drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug–drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present. We show that this occurs through an allosteric mechanism within the nucleosome, whereby defined histone adducts of one drug promote reaction of the other drug at a distant, specific histone site. This opens up possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions.||URI:||https://hdl.handle.net/10356/87027
|DOI:||10.1038/ncomms14860||Rights:||© 2017 The Author(s) (Nature Publishing Group). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
|Appears in Collections:||SBS Journal Articles|
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