Mapping the latent CRBN-molecular glue degrader interactome
ABSTRACT Molecular glue degraders (MGDs) are a transformative modality in drug discovery. MGDs that work in concert with the E3 ligase CRL4 CRBN can degrade a range of substrates through tailored MGDs. To explore CRL4 CRBN 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 CRL4 CRBN 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.
Authors
- Yanxiang Meng (ORCID: https://orcid.org/0000-0001-7447-9788)
- Andreas Scheck (ORCID: https://orcid.org/0000-0002-2123-6499)
- Dominique Klein
- Kenji Shimada (ORCID: https://orcid.org/0000-0002-6670-3118)
- Anna M. Díaz-Rovira (ORCID: https://orcid.org/0000-0001-7720-1351)
- Pius Galli (ORCID: https://orcid.org/0009-0004-9280-9305)
- Lukas Kater
- Simone Cavadini (ORCID: https://orcid.org/0000-0003-2777-7584)
- Bruno E. Correia (ORCID: https://orcid.org/0000-0002-7377-8636)
- Jacob D. Aguirre (ORCID: https://orcid.org/0000-0001-7222-1732)
- Maximilian R. Stammnitz (ORCID: https://orcid.org/0000-0002-1704-9199)
- Alexandra M. Bendel (ORCID: https://orcid.org/0000-0001-5266-4675)
- Georg Kempf (ORCID: https://orcid.org/0000-0002-0228-6730)
- Nicolas H. Thomä (ORCID: https://orcid.org/0000-0003-2685-906X)
- Guillaume Diss (ORCID: https://orcid.org/0000-0001-9153-4523)
- Alexander Hanzl (ORCID: https://orcid.org/0000-0002-6004-2312)
- Shuhao Xiao (ORCID: https://orcid.org/0000-0002-7522-3626)
- Wei Ye (ORCID: https://orcid.org/0009-0003-6314-9793)
Institutions
- University of Basel (CH)
- Barcelona Supercomputing Center (ES)
- Barcelona Institute of Science and Technology (ES)
- Centre for Genomic Regulation (ES)
- École Polytechnique Fédérale de Lausanne (CH)
- Friedrich Miescher Institute (CH)
- Universitat Politècnica de Catalunya (ES)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-02
- DOI
- https://doi.org/10.64898/2025.12.02.691773
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00