Allosteric cross-talk in chromatin can mediate drug-drug synergy

Zenita Adhireksan, Giulia Palermo, Tina Riedel, Zhujun Ma, Reyhan Muhammad, Ursula Rothlisberger (), Paul J. Dyson () and Curt A. Davey ()
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Zenita Adhireksan: School of Biological Sciences, Nanyang Technological University
Giulia Palermo: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Tina Riedel: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Zhujun Ma: School of Biological Sciences, Nanyang Technological University
Reyhan Muhammad: School of Biological Sciences, Nanyang Technological University
Ursula Rothlisberger: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Paul J. Dyson: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Curt A. Davey: School of Biological Sciences, Nanyang Technological University

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14860

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