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

点击翻译按钮获取中文摘要

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.