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

S. Blondel, A. L. Egesipe, P. Picardi, A. L. Jaskowiak, M. Notarnicola, J. Ragot, J. Tournois, A. Le Corf, B. Brinon, P. Poydenot, P. Georges, C. Navarro, P. R. Pitrez, L. Ferreira, G. Bollot, C. Bauvais, D. Laustriat, A. Mejat, A. De Sandre-Giovannoli, N. LevyM. Bifulco, M. Peschanski, X. Nissan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere2105
JournalCell Death and Disease
Volume7
Issue number2
DOIs
Publication statusPublished - 2016

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

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