Ansgar Oberheide

Project title: Macrocycles as Molecular Glues for 14-3-3 Protein–Protein Interactions

Host Institution: Eindhoven University of Technology (TU/e)

Host Supervisor: Prof. dr. ir. Luc Brunsveld

Co-host Institution: Technical University Munich (TUM)

Co-host Supervisor: Prof. dr. Michael Sattler

Summary project: Proteins are fundamentally involved in all cellular processes and directly engaged in diseases and their emergence. Thereby, the interaction between proteins is of particular importance. The modulation of protein–protein interactions (PPI) represents a great opportunity for novel approaches and strategies in drug development. Especially the stabilization of PPIs with small molecules acting as “molecular glues” is of emerging interest to target hard-to-drug proteins. Nevertheless, the rational development of such selective PPI stabilizers is challenging due to the complexity of the interdependent, underlying biophysical processes. The “PPI Druggability” project will provide new insights and opportunities to engineer PPI stabilizers exemplified on the hub protein 14-3-3. A recently discovered macrocyclic compound that stabilizes the PPIs between 14-3-3 and certain disease-relevant client proteins will serve as a molecular tool to rationalize the biophysical principles that drive selectivity and affinity of PPI stabilization. Organic synthesis will provide a diverse set of macrocycles with novel binding motifs, which is guided by structural protein data and biophysical characterizations of the thermodynamics and kinetics of PPI modulation. Cooperative effects in ternary complex formation promise highly selective stabilization. Using the designed molecular glues as tool compounds, fundamental biophysical parameters as well as their importance for stabilization of 14-3-3 PPIs will be examined to generate a quantitative relationship between compound and PPI for both selectivity and affinity. The developed, selective stabilizers offer great potential as chemical tools to interrogate the underlying biological pathways and as starting points for further lead optimizations in medicinal chemistry.