Ono Pharma Foundation Symposium

Scaffolding proteins act as protein-interaction hubs, but have been considered nearly un-targetable by drugs and chemical probes.  The seven human isoforms of 14-3-3 are ubiquitous mediators of kinase pathways, modulating the function, stability, and subcellular localization of phosphorylated client proteins. In collaboration with the Ottmann lab (Eindhoven University of Technology), we are using fragment-based ligand discovery and structure-guided design, to systematically develop molecules that stabilize specific 14-3-3/phosphopeptide complexes.  To date, we have discovered stabilizing fragments for five important cancer targets, and are designing more potent covalent and noncovalent compounds for testing in cells.  Our long-term goal is to use these molecular probes to dissect the 14-3-3 PPI network and validate targets for therapeutic intervention.