Development of novel small molecules to target cellular pathways

Small molecules represent powerful tools to dissect physiological and pathological states of signaling pathways, yet require characterization through X-ray crystallography. This proposal encompasses the investigation of new classes of small molecules that target difficult proteins and non-typical binding sites. This includes the development of supramolecular compounds or cyclic peptides to address “non-druggable" proteins. The main collaborative research fields are tackling Ras protein signaling with structure-guided ligand design, developing inhibitors of the Ras-binding protein PDEd, screening of a novel sp3-enriched fragment library or targeting genetic regulators. Cellular signaling will also be addressed through the structural analysis of deubiquitinating enzymes or regulators of the kinetochore. Finally, we plan to crystallize membrane proteins including GPCRs in order to understand their biological function, characterize their ligand specificity and develop novel regulators.