Proteome-wide identification of the druggable CRBN interactome

To explore CRBN programmability, we tested whether reported CRBN-MGD substrates are part of a network of latent CRBN interactors, proteins capable of MGD-induced CRBN binding without detectable degradation. Leveraging highly parallel interaction measurement (GluePCA) between CRBN and zinc-fingers (ZFs), we identified ~210 ZFs bound to CRBN-pomalidomide, where top binders are already reported as degraded by dedicated MGDs.

To map latent CRBN-MGD interactions proteome-wide and define the accessible CRBN interaction space, we combined AI-derived protein surface queries (MaSIF-mimicry) with GluePCA. This pipeline identified 6 known and 43 novel CRBN-pomalidomide binders, including orthogonally validated hits. We find that these binders provide privileged starting points for MGD development.