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Mapping the latent CRBN-molecular glue degrader interactome

Galli, P.; Xiao, S.; Meng, Y.; Hanzl, A.; Bendel, A. M.; Aguirre, J. D.; Diaz-Rovira, A. M.; Stammnitz, M. R.; Kempf, G.; Kater, L.; Shimada, K.; Wei, Y.; Scheck, A.; Klein, D.; Cavadini, S.; Diss, G.; Correia, B. E.; Thomae, N. H.

2025-12-02 molecular biology
10.64898/2025.12.02.691773 bioRxiv
Show abstract

Molecular glue degraders (MGDs) are a transformative modality in drug discovery. MGDs that work in concert with the E3 ligase CRL4CRBN can degrade a range of substrates through tailored MGDs. To explore CRL4CRBN reprogrammability, we tested whether reported CRBN-MGD substrates are part of a network of latent CRBN interactors, detectable with generic CRBN-MGDs. Leveraging highly parallel interaction measurement (GluePCA) between CRL4CRBN and human 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-MGDs interactions proteome-wide, and thus define the immediately accessible CRBN target space, we combined AI-derived protein surface queries (MaSIF-mimicry) with GluePCA. This pipeline identified 6 known and 43 novel CRBN-pomalidomide binders, thereby providing privileged starting points for MGD development. We expect this binding-focused, highly parallel workflow to be readily applicable to other MGD/E3 ligase systems, extending the target landscape of this emerging drug class.

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