1. Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation
- Author
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Patrícia R. Pitrez, Anne-Laure Jaskowiak, G. Bollot, Benjamin Brinon, C. Bauvais, Paola Picardi, A. Mejat, Johana Tournois, Maurizio Bifulco, Anne-Laure Egesipe, Lino Ferreira, A. Le Corf, J. Ragot, Marc Peschanski, Sophie Blondel, A. De Sandre-Giovannoli, P. Poydenot, P. Georges, D. Laustriat, Claire Navarro, Xavier Nissan, M. Notarnicola, Nicolas Lévy, Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Università degli Studi di Salerno = University of Salerno (UNISA), IRCCS 'De Bellis', Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade de Coimbra [Coimbra], Synsight, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), FCOMP-01-2014-FEDER-041659, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Gall, Valérie, Università degli Studi di Salerno (UNISA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Blondel, S, Egesipe, A-L, Picardi, P, Jaskowiak, A-L, Notarnicola, M, Ragot, J, Tournois, J, Le Corf, A, Brinon, B, Poydenot, P, Georges, P, Navarro, C, Pitrez, P R, Ferreira, L, Bollot, G, Bauvais, C, Laustriat, D, Mejat, A, De Sandre-Giovannoli, A, Levy, N, Bifulco, Maurizio, Peschanski, M, and Nissan, X
- Subjects
0301 basic medicine ,Cancer Research ,Farnesyl pyrophosphate ,LMNA ,chemistry.chemical_compound ,0302 clinical medicine ,Progeria ,Osteogenesis ,Stem cell ,integumentary system ,Cell Differentiation ,Geranyltranstransferase ,Lamin Type A ,Progerin ,farnesylation ,3. Good health ,Molecular Docking Simulation ,Biochemistry ,030220 oncology & carcinogenesis ,[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Protein farnesylation ,Original Article ,lipids (amino acids, peptides, and proteins) ,Pluripotent Stem Cells ,Premature aging ,congenital, hereditary, and neonatal diseases and abnormalities ,Immunology ,Protein Prenylation ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,Small Molecule Libraries ,Structure-Activity Relationship ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,medicine ,Farnesyltranstransferase ,Humans ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Binding Sites ,organic chemicals ,nutritional and metabolic diseases ,Cell Biology ,medicine.disease ,Protein Structure, Tertiary ,Farnesylation Process ,Pyrimidines ,030104 developmental biology ,chemistry ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,aminopyrimidines ,Cancer research ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Protein prenylation - 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.
- Published
- 2016