Drugging the 14-3-3 interactome –
Making intrinsically disordered proteins druggable
Prof. Luc Brunsveld
Intrinsically Disordered Proteins (IDPs) represent one of drug discovery’s major challenges. Due to their high degree of conformational freedom, IDPs have no defined pockets for binding small molecules. Molecular glues that can strengthen protein-protein interactions (PPIs) are a revolutionary technology for drug discovery. The hub protein 14-3-3 regulates many IDPs and ID domains via its PPIs. Stabilization of 14-3-3 PPIs with small molecular glues provides a unique entry to render IDPs druggable.
The lack of mechanistically understanding PPI stabilization impedes systematically identifying molecular glues and limits progress to drug IDPs.
Via a combination of mechanistic studies into 14-3-3 PPIs stabilization and the development of novel molecular concepts to drug the composite pockets of 14-3-3 PPIs, we aim to unlock the 14-3-3 interactome for novel drug discovery, with a special focus on the three-body-challenge (2 different proteins and a molecular glue).
Our group performs chemical biology studies on 14-3-3 PPIs with the aim to enable innovative medicinal chemistry entries for ‘molecular glues’ for PPIs. The presentation will highlight a combination of chemical biology and medicinal chemistry approaches to help to unravel the underlying complex interaction mechanisms. This conceptual approach to PPIs allows to recognize and apply supramolecular concepts such as multivalency and cooperativity within the context of drug discovery and as leading principles in for example compound optimization and selectivity towards specific PPI. Specific examples regarding the 14-3-3 PPI with the Estrogen Receptor, Tau and ChREBP will be highlighted to illustrate the functionality of 14-3-3 molecular glues on the cellular level and beyond.