title: Insights into the interaction of high potency inhibitor IRC-083864 with phosphatase CDC25.
abstract: CDC25 phosphatases play a crucial role in cell cycle regulation. They have been found to be over-expressed in various human tumours and to be valuable targets for cancer treatment. Here, we report the first model of binding of the most potent CDC25 inhibitor to date, the bis-quinone IRC-083864, into CDC25B obtained by combining molecular modeling and NMR studies. Our study provides new insights into key interactions of the catalytic site inhibitor and CDC25B in the absence of any available experimental structure of CDC25 with a bound catalytic site inhibitor. The docking model reveals that IRC-083864 occupies both the active site and the inhibitor binding pocket of the CDC25B catalytic domain. NMR saturation transfer difference and WaterLOGSY data indicate the binding zones of the inhibitor and support the docking model. Probing interactions of analogues of the two quinone units of IRC-083864 with CDC25B demonstrate that IRC-083864 competes with each monomer. Proteins 2017; 85:593-601. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, 45 rue des Saints-Pères, Paris, 75006, France.
authors.forename: Manal
authors.initials: M
authors.lastname: Sarkis
authors.affiliation: Molécules Thérapeutiques in silico, INSERM U973, Université Paris Diderot, PRES Sorbonne Paris Cité, 35 rue Hélène Brion, Paris cedex 13, 75205, France.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, 45 rue des Saints-Pères, Paris, 75006, France.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Dasso Lang
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, 45 rue des Saints-Pères, Paris, 75006, France.
authors.forename: Maryse
authors.initials: M
authors.lastname: Jaouen
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, 45 rue des Saints-Pères, Paris, 75006, France.
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Sari
authors.affiliation: Ipsen Innovation, 5 avenue du Canada, Les Ulis, 91940, France.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Galcéra
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, 45 rue des Saints-Pères, Paris, 75006, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Ethève-Quelquejeu
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, 45 rue des Saints-Pères, Paris, 75006, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, 45 rue des Saints-Pères, Paris, 75006, France.
authors.forename: Gildas
authors.initials: G
authors.lastname: Bertho
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, 45 rue des Saints-Pères, Paris, 75006, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Braud
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry*; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry*; D020134:Catalytic Domain; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D062105:Molecular Docking Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C535248:2-(2,5-difluorophenyl)-6-((3-(methyl(3-((2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino)propyl)amino)propyl)amino)-1,3-benzoxazole-4,7-dione; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D001583:Benzoxazoles; D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases
keywords: STD-NMR; WaterLOGSY; cancer; docking; protein-ligand binding