ChemBioID - An integrated chemical biology workflow for the investigation of proximity-induced pharmacology of BIRC2 by the compounds AZD5582 and GDC0152

ABSTRACT: Modulation of protein-protein interactions with small molecules represents an emerging area of interest in drug discovery, enabling new therapeutic paradigms unprecedented with other drug classes such as catalytic enzyme inhibitors. Immunomodulatory drugs are a prime example for proximity-induced pharmacology where in the case of multiple myeloma, degradation of oncogenic transcription factors is achieved via recruitment of an E3 ligase complex. Here, we present a streamlined workflow for profiling small molecule degraders, integrating proteomics-based techniques such as proximity labelling, in-cell interaction validation assays, ubiquitination analysis and protein degradation monitoring. Application of this combined approach to a set of degraders enabled us to identify known and novel IMiD-dependent CRBN binders, thereby revealing the extended recruitment capacity of these compounds and raising important questions about potential degrader pharmacology beyond the dogma of recruitment, ubiquitination and degradation. This project is part of the IMI EUbOPEN project.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Matthias Gstaiger  

LAB HEAD: Matthias Gstaiger

PROVIDER: PXD056535 | Pride | 2025-04-30

REPOSITORIES: Pride