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bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.11.612438
preprint
1
Article
Unveiling the hidden interactome of CRBN molecular glues with chemoproteomics
Baek Kheewoong
Metivier Rebecca J.
Roy Burman Shourya S.
Bushman Jonathan W.
Lumpkin Ryan J.
Abeja Dinah M.
Lakshminarayan Megha
Yue Hong
Ojeda Samuel
Verano Alyssa L.
Gray Nathanael S.
Donovan Katherine A.
Fischer Eric S.
15 9 2024
2024.09.11.612438https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.11.612438
nihpp-2024.09.11.612438.pdf
SUMMARY

Targeted protein degradation and induced proximity refer to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of glues remains challenging, unbiased discovery methods are needed to unveil hidden chemical targets. Here we establish a high throughput affinity purification mass spectrometry workflow in cell lysates for the unbiased identification of molecular glue targets. By mapping the targets of 20 CRBN-binding molecular glues, we identify 298 protein targets and demonstrate the utility of enrichment methods for identifying novel targets overlooked using established methods. We use a computational workflow to estimate target confidence and perform a biochemical screen to identify a lead compound for the new non-ZF target PPIL4. Our study provides a comprehensive inventory of targets chemically recruited to CRBN and delivers a robust and scalable workflow for identifying new drug-induced protein interactions in cell lysates.
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