Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 47, Issue -, Pages 239-254Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.10.051
Keywords
Met RTK; Met signaling inhibitor; Inhibitor binding modes; Aminoacid-amide derivatives; Anti-tumor agents; Imidazo[2,1-b]benzothiazol-2-ylphenylmoiety
Categories
Funding
- INCa (Insitut National du Cancer)
- ARC (Association pour la recherche contre le cancer)
- FRM (Fondation pour la recherche medicale)
- FdF (Fondation de France)
- Fondation Bettencourt-Schueller
- Marie Curie Host Fellowship for the Transfer of Knowledge [MTKD-CT-2004-509804]
- Protisvalor
- Valorpaca
- Oseo
- Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR)
- Spanish Ministry of Science and Innovation [CTQ2009-07021/BQU]
- AGAUR, Generalitat de Catalunya [2009-SGR-111]
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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. (C) 2011 Elsevier Masson SAS. All rights reserved.
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