title: Vascular disrupting activity and the mechanism of action of EHT 6706, a novel anticancer tubulin polymerization inhibitor.
abstract: Tumor blood vessels are an important emerging target for anticancer therapy. Here, we characterize the in vitro antiproliferative and antiangiogenic properties of the synthetic small molecule, 7-ethoxy-4-(3,4,5-trimethoxybenzyl)isoquinolin-8-amine dihydrochloride, EHT 6706, a novel microtubule-disrupting agent that targets the colchicine-binding site to inhibit tubulin polymerization. At low nM concentrations, EHT 6706 exhibits highly potent antiproliferative activity on more than 60 human tumor cell lines, even those described as being drug resistant. EHT 6706 also shows strong efficacy as a vascular-disrupting agent, since it prevents endothelial cell tube formation and disrupts pre-established vessels, changes the permeability of endothelial cell monolayers and inhibits endothelial cell migration. Genome-wide transcriptomic analysis of EHT 6706 effects on human endothelial cells shows that the antiangiogenic activity elicits gene deregulations of antiangiogenic pathways. These findings indicate that EHT 6706 is a promising tubulin-binding compound with potentially broad clinical antitumor efficacy.
authors.affiliation: Therapeutic Division, Exonhit S.A., 63-65 Bd Massena, 75013 Paris, France. anne-sophie.casagrande@exonhit.com
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Belzacq-Casagrande
authors.forename: Florence
authors.initials: F
authors.lastname: Bachelot
authors.forename: Catherine
authors.initials: C
authors.lastname: De Oliveira
authors.forename: Séverine
authors.initials: S
authors.lastname: Coutadeur
authors.forename: Florence
authors.initials: F
authors.lastname: Maurier-Mahé
authors.forename: Emeline
authors.initials: E
authors.lastname: Throo
authors.forename: Cédric
authors.initials: C
authors.lastname: Chauvignac
authors.forename: Laure
authors.initials: L
authors.lastname: Pognante
authors.forename: Angélique
authors.initials: A
authors.lastname: Petibon
authors.forename: Thierry
authors.initials: T
authors.lastname: Taverne
authors.forename: Eric
authors.initials: E
authors.lastname: Beausoleil
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leblond
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Pando
authors.forename: Laurent
authors.initials: L
authors.lastname: Désiré
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003078:Colchicine / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D018432:Drug Resistance, Multiple; D020869:Gene Expression Profiling; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D020411:Oligonucleotide Array Sequence Analysis; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: C579423:7-ethoxy-4-(3,4,5-trimethoxybenzyl)isoquinolin-8-amine; D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007546:Isoquinolines; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine