title: Identification of Noncompetitive Inhibitors of Cytosolic 5'-Nucleotidase II Using a Fragment-Based Approach.
abstract: We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hematological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors. Biological evaluation in cancer cell lines showed synergic effect with selected anticancer drugs. Structural studies using X-ray crystallography lead to the identification of new binding sites for two derivatives and of a new crystal form showing important domain swapping. Altogether, the strategy developed herein allowed identifying new original noncompetitive inhibitors against cN-II that act in a synergistic manner with well-known antitumoral agents.
authors.affiliation: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), FRE 3689 CNRS, Université de Montpellier , 1919 route de Mende, 34293 Montpellier cedex 5, France.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Marton
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCM , Campus Triolet, cc1705, Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Guillon
authors.affiliation: Institut des Sciences Analytiques, UMR 5280 CNRS, Université Lyon 1 , ENS de Lyon, 5 rue de la Doua, 69100 Villeurbanne, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Krimm
authors.affiliation: Institut de Biologie et Chimie des Protéines FR3302, Molecular and Structural Bases of Infectious Diseases UMR 5086 CNRS, Université Lyon 1 , 7 Passage du Vercors, 69367 Lyon, France.
authors.lastname: Preeti
authors.affiliation: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), FRE 3689 CNRS, Université de Montpellier , 1919 route de Mende, 34293 Montpellier cedex 5, France.
authors.forename: Rahila
authors.initials: R
authors.lastname: Rahimova
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCM , Campus Triolet, cc1705, Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: David
authors.initials: D
authors.lastname: Egron
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université Lyon 1 , 69008 Lyon, France.
authors.forename: Lars P
authors.initials: LP
authors.lastname: Jordheim
authors.affiliation: Institut de Biologie et Chimie des Protéines FR3302, Molecular and Structural Bases of Infectious Diseases UMR 5086 CNRS, Université Lyon 1 , 7 Passage du Vercors, 69367 Lyon, France.
authors.forename: Nushin
authors.initials: N
authors.lastname: Aghajari
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université Lyon 1 , 69008 Lyon, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCM , Campus Triolet, cc1705, Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Périgaud
authors.affiliation: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), FRE 3689 CNRS, Université de Montpellier , 1919 route de Mende, 34293 Montpellier cedex 5, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Lionne
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCM , Campus Triolet, cc1705, Place Eugène Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Peyrottes
authors.affiliation: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), FRE 3689 CNRS, Université de Montpellier , 1919 route de Mende, 34293 Montpellier cedex 5, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chaloin
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D062126:Databases, Chemical; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001565:Benzoates; D007093:Imidazoles; D009281:Naphthalenes; D011687:Purines; D011758:Pyrroles; D015720:5'-Nucleotidase; C508048:NT5C2 protein, human