Unveiling the hidden interactome of CRBN molecular glues with chemoproteomics

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. H...

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Published in:bioRxiv
Main Authors: Baek, Kheewoong, Metivier, Rebecca J, Roy Burman, Shourya S, Bushman, Jonathan W, Yoon, Hojong, Lumpkin, Ryan J, Abeja, Dinah M, Lakshminarayan, Megha, Yue, Hong, Ojeda, Samuel, Verano, Alyssa L, Gray, Nathanael S, Donovan, Katherine A, Fischer, Eric S
Format: Journal Article Paper
Language:English
Published: United States Cold Spring Harbor Laboratory 04.10.2024
Edition:1.2
Subjects:
Cancer Biology
cereblon
E3 ligase
proteomics
PROTAC
targeted protein degradation
molecular glue
IMiD
PPIL4
degrader
ubiquitin
ISSN:2692-8205, 2692-8205
Online Access:Get full text
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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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Competing Interest Statement: E.S.F. is a founder, scientific advisory board (SAB) member, and equity holder of Civetta Therapeutics, Proximity Therapeutics, Stelexis Biosciences, and Neomorph, Inc. (also board of directors). He is an equity holder and SAB member for Avilar Therapeutics, Photys Therapeutics, and Ajax Therapeutics and an equity holder in Lighthorse Therapeutics and Anvia Therapeutics. E.S.F. is a consultant to Novartis, EcoR1 capital, Odyssey and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, Bayer and Astellas. K.A.D receives or has received consulting fees from Kronos Bio and Neomorph Inc. N.S.G. is a founder, science advisory board member (SAB) and equity holder in Syros, C4, Allorion, Lighthorse, Inception, Matchpoint, Shenandoah (board member), Larkspur (board member) and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, Springworks, Interline and Sanofi.
ISSN:2692-8205
2692-8205
DOI:10.1101/2024.09.11.612438