Small molecular weight interfering substances of the Met-Gab1 and the Wnt-ß-catenin signaling pathways

Met-Gab 1和Wnt-β-连环蛋白信号通路的失调已显示促进人类癌症的形成和进展。到目前为止，还没有Wnt抑制剂进入临床试验，现有的Met抑制剂针对激酶结构域，缺乏特异性。我们已经筛选了小分子量化合物，其（i）干扰Met与介导所有Met生物学效应的多接头蛋白Gab 1的相互作用，和（ii）干扰β-连环蛋白与其转录配偶体TCF 4的相互作用，TCF 4介导所有经典Wnt信号。在初始Met或β-连环蛋白依赖性生物测定中测试这些化合物，并且现在将在更先进的细胞转化测定中测试在不存在细胞毒性的情况下显示良好抑制的那些化合物。最有效的化合物也将通过药物化学进行改进，并在体内测试对肿瘤生长和转移的抑制作用。应该注意的是，Met和β-连环蛋白途径之间存在桥梁：Met导致β-连环蛋白易位到细胞核，并且Met是Wnt靶基因。通过这两个项目，我们希望证明干扰蛋白质-蛋白质相互作用有可能选择用于干扰发育信号通路和潜在癌症治疗的先导化合物。

De-regulation of both the Met-Gab1 and Wnt-ß-catenin signaling pathways have been shown to promote the formation and progression of human cancers. Up to now no Wnt inhibitor has entered clinical trials and existing Met inhibitors are directed against the kinase domain and suffer from lack of specificity. We have screened for small molecular weight compounds that (i) interfere with the interaction of Met with the multiadaptor protein Gab1 that mediates all of Met biological effects and (ii) with the interaction of ß-catenin with its transcriptional partner TCF4 that mediates all canonical Wnt Signals. These compounds were tested in initial Met or ß-catenin dependent biological assays and those that showed good inhibition in the absence of cytotoxicity will now be tested in more advanced cellular transformation assays. The most effective compounds will also be improved by medicinal chemistry and tested for inhibition of tumour growth and metastasis in vivo. It should be noted that bridges between Met and ß-catenin pathways exist: Met causes ß-catenin translocation to the nucleus, and Met is a Wnt target gene. With these two projects we want to demonstrate that interfering with protein-protein interaction has a potential to select lead compounds for interfering with developmental signaling pathways and for potential cancer therapy.