2. Academic Validation
  3. Dual inhibitors of the pro-survival proteins Bcl-2 and Mcl-1 derived from natural compound meiogynin A

Dual inhibitors of the pro-survival proteins Bcl-2 and Mcl-1 derived from natural compound meiogynin A

  • Eur J Med Chem. 2018 Mar 25:148:26-38. doi: 10.1016/j.ejmech.2018.01.100.
Alma Abou Samra 1,  Aude Robert 2,  Crystal Gov 2,  Loëtitia Favre 2,  Laure Eloy 1,  Eric Jacquet 1,  Jérôme Bignon 1,  Joëlle Wiels 2,  Sandy Desrat 3,  Fanny Roussi 4
Affiliations

Affiliations

  • 1 Institut de Chimie des Substances Naturelles, CNRS, ICSN UPR2301, Université Paris-Saclay, 91198, Gif-sur-Yvette, France.
  • 2 UMR CNRS 8126, Univ. Paris Sud, Université Paris-Saclay, Institut Gustave Roussy, 114 rue Edouard-Vaillant, 94805, Villejuif Cedex, France.
  • 3 Institut de Chimie des Substances Naturelles, CNRS, ICSN UPR2301, Université Paris-Saclay, 91198, Gif-sur-Yvette, France. Electronic address: sandy.desrat@cnrs.fr.
  • 4 Institut de Chimie des Substances Naturelles, CNRS, ICSN UPR2301, Université Paris-Saclay, 91198, Gif-sur-Yvette, France. Electronic address: fanny.roussi@cnrs.fr.
PMID: 29453135 DOI: 10.1016/j.ejmech.2018.01.100
Abstract

Thirty analogues of natural meiogynin A, a pan-Bcl-2 inhibitor, were prepared in order to elaborate cytotoxic compounds on specific Cancer cells overexpressing one or more proteins of the Bcl-2 Family. The interaction of all the new analogues with Bcl-xL, Mcl-1 and Bcl-2 proteins was first evaluated by fluorescence polarization assay (FPA) and showed that modulation of the lateral chain has a dramatic impact as subtle changes significantly modify the activity on the target proteins. The acetoxymethyl prodrugs of the two most active compounds were then elaborated to determine their cytotoxicity on B cell lines. A strong cytotoxic effect on BL2, RS4;11 and H929 cells was observed with a triazole prodrug that induces Apoptosis.

Keywords

Apoptosis; Bcl-2 proteins; Cancer; Natural compound; Protein-protein interactions.

Figures