Forschungsseminar Vortrag von Dr. Klemens Hoegenauer

Every cell needs to build up and disassemble proteins at various stages to stay healthy or respond to certain signals. Protein disassembly takes place in the proteasome after proteins have been tagged with polyubiquitin chains by E3 ligases. Redirecting E3 ligases artificially towards proteins that the cellular machinery would normally not tag for disassembly, also known as targeted protein degradation, has lately emerged as a promising alternative to traditional, occupancy driven pharmacology, e.g. an enzyme inhibitor. Although the field has expanded tremendously over the last years, the choice of E3 ligases remains limited. Here, we report the discovery of ligands to the novel ligase TRIM58. Screening and validation using various biophysical methods led to the identification of the TRIM58 ligand TRIM-473. A crude structure-activity-relationship SAR around the chemotype was established. The X-ray co-crystal structure of TRIM58 in complex with TRIM-473 gave insights to the binding mode and potential exit vectors for degrader design.