FUSIONBREAK: Targeting the Undruggable PAX3-FOXO1 Oncofusion through Chemical Biology Strategies

• Applicant: Dr. Tom Schulz
• Subject Area: Biological and Biomimetic Chemistry ; Biochemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566927020

Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric cancer driven by oncogenic fusion proteins like PAX3-FOXO1, for which no effective targeted therapies exist. Traditional small molecule inhibitors have failed to directly target PAX3-FOXO1 due to its disordered structure and lack of defined binding pockets, highlighting the urgent need for innovative therapeutic strategies. This project leverages a small-molecule microarray (SMM) ligand discovery platform to identify and optimize small-molecule binders of PAX3-FOXO1 as starting points for the development of proteolysis-targeting chimeras (PROTACs). By integrating state-of-the-art ligand discovery with targeted protein degradation, this work has the potential to establish a novel treatment modality for fusion-driven pediatric cancers. Beyond its translational potential, this research will provide essential insights into the biological function and vulnerabilities of PAX3-FOXO1, offering a foundation for future targeting strategies.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Angela Koehler, Ph.D.