Please use this identifier to cite or link to this item:
Title: Identification of new aminoacid amides containing the imidazo[2,1-b]benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling.
Authors: Furlan, A.
Colombo, F.
Kover, A.
Issaly, N.
Tintori, Cristina
Angeli, Lucilla
Leroux, V.
Letard, S.
Amat, M.
Asses, Y.
Maigret, B.
Dubreuil, P.
Botta, Maurizio 
Dono, R.
Bosch, J.
Piccolo, O.
Passarella, D.
Maina, F.
Keywords: Met RTK Met signaling inhibitor Inhibitor binding modes Aminoacid-amide derivatives Anti-tumor agents Imidazo[2; 1-b]benzothiazol-2-ylphenyl moiety
Issue Date: 2012
Project: None 
The Met receptor tyrosine kinase is a promising target in anticancer therapies for its role during tumor evolution and resistance to treatment. It is characterized by an unusual structural plasticity as its active site accepts different inhibitor binding modes. Such feature can be exploited to identify distinct agents targeting tumor dependence and/or resistance by oncogenic Met. Here we report the identification of bioactive agents, featuring a new 4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl moiety, targeting cancer cells dependent on oncogenic Met. One of these compounds (7c; Triflorcas) impairs survival, anchorage-independent growth, and in vivo tumorigenesis, without showing side effects. Our medicinal chemistry strategy was based on an in-house Met-focused library of aminoacid-amide derivatives enriched through structure-based computer modeling, taking into account the Met multiple-binding-mode feature. Altogether, our findings show how a rational structure-based drug design approach coupled to cell-based drug evaluation strategies can be applied in medicinal chemistry to identify new agents targeting a given oncogenic-dependency setting. Copyright © 2011 Elsevier Masson SAS. All rights reserved.
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2011.10.051
Appears in Collections:Publications

Show full item record

Google ScholarTM



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.