Development of novel molecular tools for FZDs

• Applicant: Dr. Lukas Grätz
• Subject Area: Pharmacology ; Pharmacy
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504098926

Together with the Smoothened receptor, the 10 Frizzleds (FZD1-10) form the class F within the superfamily of G protein-coupled receptors (GPCRs). In humans, FZD1-10 act as important targetes for the 19 secreted Wingless/Int-1 lipoglycoproteins, Wnts for short. On the one hand, this Wnt signaling system is essential for embryonic development, but also retains an important role in adults, e.g. in the regulation of stem cell function or during organogenesis. However, if this signaling system is dysregulated, e.g. through excessive activation, a wide variety of pathological phenomena, such as tumors or neurodegenerative diseases, are the result. Therefore, targeting a dysfunctional Wnt signaling system, e.g. by blocking FZDs, represents an attractive, but not yet exploited possibility for the therapy of such diseases.Despite groundbreaking progress in FZD research over the last years, it has not yet been possible to develop highly effective FZD-addressing agents and bring them to market. This is mainly due to the large number of still unresolved questions, especially regarding the mechanisms of FZD activation and the subsequent signaling cascades.It is the aim of the project to develop new molecular tools for FZDs, with a special focus on FZD5, in order to answer these questions. Therefore, using different cellular assay systems, high-throughput campaigns will be performed to identify highly potent scaffolds of small molecule FZD5 ligands. An extended pharmacological profile will be established for those ligands by investigating their subtype-selectivity, signaling specificity and their effect on FZD5-dependent tumor cell lines. In the course of the project, additional assay techniques will be developed in order to facilitate the study of the molecular pharmacology of FZDs.The tools developed during the project will contribute significantly to a better understanding of mechanisms behind ligand binding and activation of this fascinating receptor class, e.g. by enabling structural biology studies of FZD/ligand complexes. Additionally, the discovered novel scaffolds of FZD ligands will also provide an excellent starting point for the development of FZD-targeting drugs.

• DFG Programme: WBP Fellowship
• International Connection: Sweden
• Host: Professor Gunnar Schulte, Ph.D.