Unveiling the hidden interactome of CRBN molecular glues with chemoproteomics.

bioRxiv : the preprint server for biology
Authors
Keywords
Abstract

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.

Year of Publication
2024
Journal
bioRxiv : the preprint server for biology
Date Published
10/2024
ISSN
2692-8205
DOI
10.1101/2024.09.11.612438
PubMed ID
39314457
Links