title: Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation.
abstract: 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.
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Blondel
authors.affiliation: CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.
authors.forename: A-L
authors.initials: AL
authors.lastname: Egesipe
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Via Allende, Baronissi Salerno 84081, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Picardi
authors.affiliation: CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.
authors.forename: A-L
authors.initials: AL
authors.lastname: Jaskowiak
authors.affiliation: Laboratory of Nutritional Biochemistry, National Institute for Digestive Diseases "S. de Bellis", Castellana Grotte, Bari 70013, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Notarnicola
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Ragot
authors.affiliation: CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.
authors.forename: J
authors.initials: J
authors.lastname: Tournois
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Le Corf
authors.affiliation: CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.
authors.forename: B
authors.initials: B
authors.lastname: Brinon
authors.affiliation: CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.
authors.forename: P
authors.initials: P
authors.lastname: Poydenot
authors.affiliation: CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.
authors.forename: P
authors.initials: P
authors.lastname: Georges
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Navarro
authors.affiliation: CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Largo Marques de Pombal, Coimbra 3004-517, Portugal.
authors.forename: P R
authors.initials: PR
authors.lastname: Pitrez
authors.affiliation: CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Largo Marques de Pombal, Coimbra 3004-517, Portugal.
authors.forename: L
authors.initials: L
authors.lastname: Ferreira
authors.affiliation: SYNSIGHT, a/s IncubAlliance 86 rue de Paris Orsay 91400, France.
authors.forename: G
authors.initials: G
authors.lastname: Bollot
authors.affiliation: SYNSIGHT, a/s IncubAlliance 86 rue de Paris Orsay 91400, France.
authors.forename: C
authors.initials: C
authors.lastname: Bauvais
authors.affiliation: CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, Evry Cedex 91030, France.
authors.forename: D
authors.initials: D
authors.lastname: Laustriat
authors.affiliation: Ecole Normale Supérieure de Lyon, Laboratoire de Biologie Moléculaire de la Cellule, UMR 5239 CNRS/ENS Lyon/UCBL, 46 Allée d'Italie, Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Mejat
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: De Sandre-Giovannoli
authors.affiliation: 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.
authors.forename: N
authors.initials: N
authors.lastname: Levy
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Via Allende, Baronissi Salerno 84081, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bifulco
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Peschanski
authors.affiliation: 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.
authors.forename: X
authors.initials: X
authors.lastname: Nissan
mesh_terms: D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D062105:Molecular Docking Simulation; D010012:Osteogenesis / Q000187:drug effects; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011371:Progeria / Q000378:metabolism / Q000473:pathology*; D017368:Protein Prenylation / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D034904:Lamin Type A; D011743:Pyrimidines; D054852:Small Molecule Libraries; C090764:prelamin A; C012180:2-aminopyrimidine; D051228:Geranyltranstransferase; D051231:Farnesyltranstransferase