Small molecular weight interfering substances of the Met-Gab1 and the Wnt-ß-catenin signaling pathways
Zusammenfassung der Projektergebnisse
Compound LF3, a 4-thioureido-benzenesulfonamide derivative, was identified from high-throughput screening, which showed potent inhibition of protein-protein interaction of TCF4 and β-catenin. Medicinal chemistry identified an essential core structure of LF3 and residues that could not be exchanged without loss of activity. LF3 inhibited Wnt-related characteristics of cancer cells, like high cell motility and proliferation as well as the induction of Wnt-specific target genes. LF3 did not interfere with cadherin-mediated cell-cell adhesion. Remarkably, the self-renewal capacity of colon cancer stem cells was also blocked by LF3, as shown by reduced sphere formation. LF3 also reduced tumor growth and induced differentiation of colon cancer stem cells in mouse xenografts. Thus, LF3 is a specific inhibitor of canonical Wnt signaling, and has potential to be further developed for preclinical studies. We also developed small-molecule inhibitors that target protein-protein interaction of MET with the multi-adaptor protein GAB1. Two inhibitors, RG1 and RG3, were identified through high-throughput screenings based on AlphaScreen and ELISA. The hits also showed potent inhibition of MET signaling in pathway-specific assays such as scatter assay and in vitro-branching morphogenesis assay. Further efforts based on medicinal chemistry and in-depth structural information are now required to increase the efficacies of RG1 and RG3. We have thus established novel high-throughput methods to discover inhibitors of protein-protein interaction in the HGF/MET pathway. Also, we were able to identify potent and druglike inhibitors of the HGF/GAB1 interaction that have potential to be developed further as cancer-interfering drugs.
