KDM4B Degraders (SJ-24-0004)

St. Jude Reference #SJ-24-0004

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 which could overlook non-essential neosubstrates of potential therapeutic value. To address this concern, researchers at St. Jude developed a high-throughput proteome-wide MGD screening platform utilizing label-free, data-independent acquisition mass spectrometry (DIA-MS) for integrated proteomics and ubiquitinomics analysis with 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. Their findings considerably expanded 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, allowing for better selectivity and stronger and more sustained efficacy.

Keywords

KDM4B, G3BP2, VCL Degrader, molecular glue degraders (MGDs), small molecule, ubiquitin-proteasome system, target proteins, ‘druggable’ pocket, screening-based, neosubstrate, high-throughput proteome-wide MGD screening, label-free, data-independent, mass spectrometry (DIA-MS), integrated proteomics, ubiquitinomics, CRBN-ligand, phenyl glutarimide

Granted patents or published applications

Pending

Related scientific references

Unbiased mapping of cereblon neosubstrate landscape by high-throughput proteomics Martin Steger, Gisele Nishiguchi, Qiong Wu, Bjoern Schwalb, Bachuki Shashikadze, Kevin McGowan, Zhe Shi, Jeanine Price, Anand Mayasundari, Lei Yang, Anastasia H. Bednarz, Sophie Machata, Tobias Graef, Denis Bartoschek, Vadim Demichev, Uli Ohmayer, Jun Yang, Henrik Daub, Zoran Rankovic doi: https://doi.org/10.1101/2024.10.18.618633

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