Aix-Marseille Univ, IBDML, CNRS UMR 6216, Parc Scientifique de Luminy, Case 907, 13288 Marseille, France.
Eur J Med Chem. 2012 Jan;47(1):239-54. doi: 10.1016/j.ejmech.2011.10.051. Epub 2011 Nov 4.
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.
间质表皮转化因子（MET）受体酪氨酸激酶在肿瘤进化和治疗耐药中起重要作用，是抗肿瘤治疗的一个有前途的靶点。它的一个显著特征是结构的非常规可塑性，因为其活性位点可以接受不同的抑制剂结合模式。这种特征可以被利用来识别针对致癌性 MET 的肿瘤依赖性和/或耐药性的不同药物。在这里，我们报告了具有新的 4-(咪唑并[2,1-b]苯并噻唑-2-基)苯基部分的生物活性化合物的鉴定，这些化合物针对依赖致癌性 MET 的癌细胞。其中一种化合物（7c；Triflorcas）在没有显示副作用的情况下，损害了癌细胞的存活、锚定非依赖性生长和体内肿瘤发生。我们的药物化学策略是基于我们内部的 MET 为重点的氨基酸酰胺衍生物文库，通过基于结构的计算机建模进行了丰富，考虑到了 MET 的多种结合模式特征。总之，我们的研究结果表明，如何将基于合理结构的药物设计方法与基于细胞的药物评估策略相结合，应用于药物化学，以鉴定针对特定致癌依赖性的新药物。
