Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation.

Autor: Blondel S; INSERM U861, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.; UEVE, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Egesipe AL; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Picardi P; Department of Medicine and Surgery, University of Salerno, Via Allende, Baronissi Salerno 84081, Italy., Jaskowiak AL; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Notarnicola M; Laboratory of Nutritional Biochemistry, National Institute for Digestive Diseases 'S. de Bellis', Castellana Grotte, Bari 70013, Italy., Ragot J; INSERM U861, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.; UEVE, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Tournois J; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Le Corf A; INSERM U861, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.; UEVE, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Brinon B; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Poydenot P; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Georges P; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Navarro C; Aix Marseille Université, UMR S 910: Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine Timone, Marseille, France.; INSERM, UMR S 910: Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine, Marseille, France., Pitrez PR; CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Largo Marques de Pombal, Coimbra 3004-517, Portugal., Ferreira L; CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Largo Marques de Pombal, Coimbra 3004-517, Portugal., Bollot G; SYNSIGHT, a/s IncubAlliance 86 rue de Paris Orsay 91400, France., Bauvais C; SYNSIGHT, a/s IncubAlliance 86 rue de Paris Orsay 91400, France., Laustriat D; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Mejat A; Ecole Normale Supérieure de Lyon, Laboratoire de Biologie Moléculaire de la Cellule, UMR 5239 CNRS/ENS Lyon/UCBL, 46 Allée d'Italie, Lyon, France., De Sandre-Giovannoli A; Aix Marseille Université, UMR S 910: Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine Timone, Marseille, France.; INSERM, UMR S 910: Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine, Marseille, France., Levy N; Aix Marseille Université, UMR S 910: Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine Timone, Marseille, France.; INSERM, UMR S 910: Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine, Marseille, France., Bifulco M; Department of Medicine and Surgery, University of Salerno, Via Allende, Baronissi Salerno 84081, Italy., Peschanski M; INSERM U861, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.; UEVE, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France., Nissan X; INSERM U861, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.; UEVE, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2016 Feb 18; Vol. 7, pp. e2105. Date of Electronic Publication: 2016 Feb 18.
DOI: 10.1038/cddis.2015.374
Abstrakt: Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene (c.1824C>T) leading to the production of a toxic form of the prelamin A protein called progerin. Because farnesylation process had been shown to control progerin toxicity, in this study we have developed a screening method permitting to identify new pharmacological inhibitors of farnesylation. For this, we have used the unique potential of pluripotent stem cells to have access to an unlimited and relevant biological resource and test 21,608 small molecules. This study identified several compounds, called monoaminopyrimidines, which target two key enzymes of the farnesylation process, farnesyl pyrophosphate synthase and farnesyl transferase, and rescue in vitro phenotypes associated with HGPS. Our results opens up new therapeutic possibilities for the treatment of HGPS by identifying a new family of protein farnesylation inhibitors, and which may also be applicable to cancers and diseases associated with mutations that involve farnesylated proteins.
Databáze: MEDLINE
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