title: Allosteric cross-talk in chromatin can mediate drug-drug synergy.
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.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Zenita
authors.initials: Z
authors.lastname: Adhireksan
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Giulia
authors.initials: G
authors.lastname: Palermo
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Tina
authors.initials: T
authors.lastname: Riedel
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Zhujun
authors.initials: Z
authors.lastname: Ma
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Reyhan
authors.initials: R
authors.lastname: Muhammad
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Rothlisberger
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.|NTU Institute of Structural Biology, Nanyang Technological University, 59 Nanyang Drive, Singapore 636921, Singapore.
authors.forename: Curt A
authors.initials: CA
authors.lastname: Davey
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D001310:Auranofin / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004357:Drug Synergism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009707:Nucleosomes / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary
chemical_list: D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; D009942:Organometallic Compounds; C534678:RAPTA-T; D001310:Auranofin