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Proteome-wide identification of the druggable CRBN interactome

ABSTRACT: Molecular glue degraders (MGDs), such as pomalidomide, induce degradation of non-native substrates by the E3 ligase CRL4CRBN through its substrate receptor CRBN. 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. We expect this binding-focused workflow to be applicable to other MGD/E3 ligase systems, potentially extending the scope of this emerging drug class.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE298800 | GEO | 2026/06/08

REPOSITORIES: GEO

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CRL4(CRBN) ubiquitin ligase profiling

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