2. Academic Validation
  3. Design, synthesis and biological evaluation of conformationnally-restricted analogues of E7010 as inhibitors of tubulin assembly (ITA) and vascular disrupting agents (VDA)

Design, synthesis and biological evaluation of conformationnally-restricted analogues of E7010 as inhibitors of tubulin assembly (ITA) and vascular disrupting agents (VDA)

  • Eur J Med Chem. 2022 Dec 15;244:114809. doi: 10.1016/j.ejmech.2022.114809.
Vassili Prudhomme 1,  Mélissa Cucca 1,  Lionel Nauton 1,  Elsa Andrieu 1,  Mathilde Fereyrolles 2,  Sylvain Lamoine 2,  Clément Michelin 1,  Khalil Bennis 1,  Aurore Collin 2,  Frédéric De Ceuninck 3,  Iuliana Botez 4,  Christophe Mallet 2,  Sylvie Ducki 5
Affiliations

Affiliations

  • 1 Université Clermont Auvergne, Clermont Auvergne INP, CNRS, ICCF, 63000, Clermont-Ferrand, France.
  • 2 Université Clermont Auvergne, INSERM, NEURODOL, 63000, Clermont-Ferrand, France.
  • 3 Center for Therapeutic Innovation, Immuno-inflammatory Disease, Institut de Recherches Servier, 78290, Croissy-sur-Seine, France.
  • 4 Drug Design Small Molecules Unit, Institut de Recherches Servier, 78290, Croissy-sur-Seine, France.
  • 5 Université Clermont Auvergne, Clermont Auvergne INP, CNRS, ICCF, 63000, Clermont-Ferrand, France. Electronic address: [email protected].
PMID: 36208509 DOI: 10.1016/j.ejmech.2022.114809
Abstract

Vascular-disrupting agents (VDA) specifically target established neovasculature which results in vascular shutdown. This therapeutic strategy could improve the outcome of pathologies involving aberrant angiogenesis. Although several classes of VDA exist, inhibitors of tubulin assembly (ITA) represent the main category. A series of 21 conformationnally-restricted analogues of E7010, a known ITA-VDA, were designed and synthesised as novel inhibitors of tubulin assembly (ITA) and vascular-disrupting agents (VDA). Among them, indole 4j exhibited good potency against HUVEC and HIG-82 cell lines, as well as a good ability to inhibit tubulin assembly. Furthermore, indole 4j reduced HUVEC migration in a dose-dependent manner, indicating a vascular disrupting activity comparable to that of the gold standard, Combretastatin A4 (CA4).

Keywords

E7010; Inhibition of tubulin assembly (ITA); Vascular-disrupting agents (VDA).

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