Investigation of cereblon binding modes for targeted protein degradation

This proposal supports our research in the area of Targeted Protein Degradation (TPD) via the Ubiquitin Proteasome System (UPS). The UPS is one of the cell’s primary protein degradation pathways, allowing for the degradation of vastly different proteins. We utilize its modular architecture to hijack the cell’s UPS for the degradation of disease-related proteins with Proteolysis Targeting Chimeras (PROTACs) and Immunomodulatory Drugs (IMiDs). These classes of recently emerged drugs enable the targeting of previously undruggable proteins. Our main efforts are focused on developing new ligands for ubiquitin ligases as building blocks for next-generation PROTACs and IMiDs for the E3 ubiquitin-ligase substrate-receptor protein cereblon (CRBN). The requested beamtime will enable us to study the binding modes of our compounds and inform iterative compound optimization as part of an integrative structure-activity-relationship analysis.