MassIVE MSV000096721

Partial Public PXD059111

Unbiased mapping of cereblon neosubstrate landscape by high-throughput proteomics

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Description

Molecular glue degraders (MGDs) are small molecules that harness the ubiquitin-proteasome system to induce degradation of target proteins, including those lacking conventional druggable pockets. Given the challenges in their rational design, MGD discovery predominantly relies on screening-based approaches, such as cell viability assays. However, one potential limitation of such screening methods is the risk of overlooking non-essential neosubstrates of potential therapeutic value. To address this concern, we present a high-throughput proteome-wide MGD screening platform utilizing label-free, data-independent acquisition mass spectrometry (DIA-MS) for integrated proteomics and ubiquitinomics analysis. Processing a diverse set of 100 CRBN-ligands across two cancer cell lines reveals a broad array of neosubstrates, including 50 novel candidates validated by MS-based ubiquitinomics. These findings considerably expand the current landscape of CRBN-mediated neosubstrates. Comprehensive hit validation and structure-degradation relationship analyses guided by global proteomics, identifies highly selective and potent phenyl glutarimide-based degraders of novel neosubstrates, including KDM4B, G3BP2 and VCL, none of which contain the classical CRBN degron motif. This study demonstrates that comprehensive, high-throughput proteomic screening offers new opportunities in MGD drug discovery. [doi:10.25345/C5FB4WZ6Q] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Molecular glue degrader, cereblon, proteomics screeening, ubiquitinomics ; DatasetType:Proteomics

Contact

Principal Investigators:
(in alphabetical order) 		Zoran Rankovic, institute of cancer research, United Kingdom
Submitting User: msteger
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