Synthetic Approaches for Discovering Protein Molecular Glues

The project is focussed on accelerating the discovery of molecular glues that can stabilise interactions between proteins. Protein-protein interactions (PPI) are a challenging class of drug target to have emerged in recent years with much effort focussed on the successful development of molecules that act as inhibitors. The opposite approach of stabilising an interaction is just as valid for the treatment of many diseases. However, this presents an even bigger scientific challenge as the underlying principles are not well understood. By expanding the chemical toolkit available it will be possible to better interrogate existing examples, develop scientific models and ultimately design effective PPI stabilising molecules for drug discovery.

One major requirement for achieving this is the development of discovery platforms specifically geared toward the identification of molecules that bind at the interface of a PPI. Such compounds would provide ideal starting points for further optimisation into highly specific molecular glues. Whilst traditional drug discovery methods have an important role to play they often miss compounds exhibiting this behaviour, are costly or only suited to certain PPI systems.

This interdisciplinary chemical biology project will complement existing research activity within the Leicester Institute of Structural and Chemical Biology (LISCB) through the development of an alternative assay technology that harnesses the complexity of PPIs. Target-guided synthesis (TaGS) methodology is central to this and will be established on the PPI between 14-3-3 hub proteins and the oestrogen receptor α (ERα). 14-3-3 proteins are adaptor proteins with numerous roles in the cell and have many binding partners that are implicated in disease (ERα is important in breast cancer biology). It is the perfect test-bed system because: i) an accessible natural product stabiliser has already been well described; ii) a vast amount of structural information is at hand and; iii) two encouraging reports suggest that bio-orthogonal chemistry will be possible in the presence of 14-3-3 proteins. By careful consideration of molecular design and diversity this approach has the potential to deliver new ‘hit’ compounds that can be optimised into effective stabilisers of almost any PPI. It is envisaged that both the molecular and technological outputs of the project will have a big impact on drug discovery.