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Unveiling the hidden interactome of CRBN molecular glues

Kheewoong Baek, Rebecca J. Metivier, Shourya S. Roy Burman, Jonathan W. Bushman, Hojong Yoon, Ryan J. Lumpkin, Julia K. Ryan, Dinah M. Abeja, Megha Lakshminarayan, Hong Yue, Samuel Ojeda, Yuan Xiong, Jianwei Che, Alyssa L. Verano, Anna M. Schmoker, Nathanael S. Gray, Katherine A. Donovan () and Eric S. Fischer ()
Additional contact information
Kheewoong Baek: Boston
Rebecca J. Metivier: Boston
Shourya S. Roy Burman: Boston
Jonathan W. Bushman: Boston
Hojong Yoon: Dana-Farber Cancer Institute
Ryan J. Lumpkin: Boston
Julia K. Ryan: Boston
Dinah M. Abeja: Boston
Megha Lakshminarayan: Boston
Hong Yue: Boston
Samuel Ojeda: Boston
Yuan Xiong: Boston
Jianwei Che: Boston
Alyssa L. Verano: Boston
Anna M. Schmoker: Boston
Nathanael S. Gray: Stanford University
Katherine A. Donovan: Boston
Eric S. Fischer: Boston

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Induced proximity by molecular glues refers to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of molecular glues remains challenging, unbiased discovery methods are necessary to discover new chemical targets. Here we establish a high throughput affinity proteomics workflow leveraging E3 ligase activity-impaired CRBN-DDB1ΔB in cell lysates for the unbiased identification of molecular glue targets. By mapping the interaction landscape of CRBN-binding molecular glues, we unveil 298 protein targets and demonstrate the utility of enrichment methods for identifying targets overlooked by established methods. We use a computational workflow to estimate target confidence and perform biochemical and structural validation of uncharacterized neo-substrates. We further identify a lead compound for the previously untargeted non-zinc finger PPIL4 through a biochemical screen. Our study provides a comprehensive inventory of targets chemically recruited to CRBN and delivers a robust and scalable workflow for identifying drug-induced protein interactions in cell lysates.

Date: 2025
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DOI: 10.1038/s41467-025-62099-w

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