Unbiased mapping of cereblon neosubstrate landscape by high-throughput proteomics

Martin Steger, Gisele Nishiguchi, Qiong Wu, Bjoern Schwalb, Bachuki Shashikadze, Kevin McGowan, Marisa Actis, Anup Aggarwal, Zhe Shi, Jeanine Price, Anand Mayasundari, Lei Yang, Anastasia H. Bednarz, Sophie Machata, Tobias Graef, Denis Bartoschek, Vadim Demichev, Uli Ohmayer, Jun Yang (), Henrik Daub () and Zoran Rankovic ()
Additional contact information
Martin Steger: NEOsphere Biotechnologies GmbH
Gisele Nishiguchi: St. Jude Children’s Research Hospital
Qiong Wu: St. Jude Children’s Research Hospital
Bjoern Schwalb: NEOsphere Biotechnologies GmbH
Bachuki Shashikadze: NEOsphere Biotechnologies GmbH
Kevin McGowan: St. Jude Children’s Research Hospital
Marisa Actis: St. Jude Children’s Research Hospital
Anup Aggarwal: St. Jude Children’s Research Hospital
Zhe Shi: St. Jude Children’s Research Hospital
Jeanine Price: St. Jude Children’s Research Hospital
Anand Mayasundari: St. Jude Children’s Research Hospital
Lei Yang: St. Jude Children’s Research Hospital
Anastasia H. Bednarz: NEOsphere Biotechnologies GmbH
Sophie Machata: NEOsphere Biotechnologies GmbH
Tobias Graef: NEOsphere Biotechnologies GmbH
Denis Bartoschek: NEOsphere Biotechnologies GmbH
Vadim Demichev: Charité – Universitätsmedizin Berlin
Uli Ohmayer: NEOsphere Biotechnologies GmbH
Jun Yang: St. Jude Children’s Research Hospital
Henrik Daub: NEOsphere Biotechnologies GmbH
Zoran Rankovic: St. Jude Children’s Research Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Molecular glue degraders (MGDs) are small molecules that co-opt the ubiquitin-proteasome system to induce degradation of target proteins, including those considered undruggable. Their discovery remains challenging due to the lack of rational design strategies and limited throughput of unbiased proteome-wide screening approaches. To address this gap, we develop a high-throughput proteomics platform based on label-free, data-independent acquisition mass spectrometry (DIA-MS), enabling integrated proteomics and ubiquitinomics profiling. Screening a diverse set of 100 cereblon (CRBN)-recruiting ligands on this platform leads to identification of a broad array of novel degraders and neosubstrates. Subsequent hit validation and structure-degradation relationship analyses guided by global proteomics reveal highly selective and potent phenyl glutarimide-based degraders targeting previously uncharacterized neosubstrates such as KDM4B, G3BP2 and VCL; none of which contain the classical CRBN β-hairpin degron. These findings underscore the power of unbiased high-throughput proteomics in MGD drug discovery and reveal a substantially expanded CRBN neosubstrate landscape beyond that defined by classical immunomodulatory imid drugs (IMiDs).

Date: 2025
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DOI: 10.1038/s41467-025-62829-0

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