Low molecular weight MET antagonists
This work builds on the concept that even large protein-protein interactions involving flat surfaces may be amenable to small therapeutics if these are able to interact with small surface patches ('hot spots') that play the dominant role in binding energy. The project will search for a low molecular weight antagonist of the MET receptor and will consist of the following steps:
- A screen for MET binders to be carried out by employing a fragment library and hits from the screen will be characterised using the thermal shift method.
- Next, NMR will be employed in order to define the binding of fragments and leads to the MET receptor or its ligand. Our goal is to disrupt the high-affinity binding site and the ability of fragments to disrupt the binding of NK1 to MET will be assessed by NMR using isotope-labelled NK1 and experimental techniques.
- Selected fragments or leads will be employed for crystal soaking experiments with NK1 or MET in order to use structural data to guide the subsequent medicinal chemistry.
- A strategy for fragment assembly will be devised based on the above data and chemical synthesis. Finally, subject to suitable progress, selected lead compounds will be studied for antagonistic activity in vivo in mouse tumour models.