Organic Chemistry Seminar: Making intrinsically disordered proteins druggable with 14-3-3 molecular glues – From fragment-based drug discovery to biomolecular condensates

Abstract:

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 via phosphorylation-dependent PPIs. Stabilization of 14-3-3 PPIs with small molecular glues provides a unique entry point to render IDPs druggable.

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, including via dynamic-covalent fragment-based drug discovery, we aim to unlock the 14-3-3 interactome for novel drug discovery. The presentation will highlight a combination of chemical biology and medicinal chemistry approaches to help to unravel the underlying complex interaction mechanisms. 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.

Event Organizer: Dr. Muhammad Jbara