Identification of new aminoacid amides containing the imidazo[2,1-b]benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling

Aix-Marseille Univ, IBDML, CNRS UMR 6216, Parc Scientifique de Luminy, Case 907, 13288 Marseille, France.
European Journal of Medicinal Chemistry (Impact Factor: 3.45). 11/2011; 47(1):239-54. DOI: 10.1016/j.ejmech.2011.10.051
Source: PubMed


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.

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Available from: Flavio Maina, Oct 05, 2015
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    • "ErbB1 and PDGFRβ were two obvious candidates as they are responsible for RTK swapping. We excluded that Triflorcas acts on ErbB1 as: a) ErbB1 phosphorylation was unaffected by Triflorcas in BT474 cells (Figure S1C) [19], and b) ErbB1 is not predominantly phosphorylated in U87 cells under normal conditions (data not shown), as previously reported [27]. In contrast, we observed a drastic reduction in PDGFRβ phosphorylation when cells were exposed to Triflorcas (Figure 8D). "
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