SHP-2 Inhibitors
SHP-2 is the most important downstream signalling molecule of MET and GAB-1 for the activation of the Ras/MAP kinase pathway and the latter is responsible for motility, invasion and transformation.
This work aims to develop potent and specific inhibitors of SHP-2 for application in metastatic cancer and builds on initial studies that demonstrate both the feasibility and therapeutic potential of this approach. Putative SHP-2 inhibitors have been identified using a homology model of SHP-2 and in silico screen. The relevant compounds have been synthesised and have shown good activity in several assays including activation of the Ras/MAP kinase pathway and cell motility. The new work is divided in two blocks:
- A new screen for cell permeable SHP-2 inhibitors will be carried by the Leibniz Institute for Molecular Pharmacology in Berlin (FMP) and will consist of two components:
- an enzymatic screen and,
- a high-content, cell-based screen
- An in vivo model of SHP-2 over-expression and tumorigenesis will be developed in order to test the SHP-2 inhibitors in such a model. These studies will include pharmakokinetic and toxicological profiling of existing hits and the development of a mouse model of SHP-2 over-expression for in vivo testing of the lead compounds.