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Molecular glue degraders (MGDs) are small molecules that co-opt the ubiquitin-proteasome system to induce degradation of target proteins, including those considered undruggable. Their discovery remains challenging due to the lack of rational design strategies and limited throughput of unbiased proteome-wide screening approaches. To address this gap, we develop a high-throughput proteomics platform based on label-free, data-independent acquisition mass spectrometry (DIA-MS), enabling integrated proteomics and ubiquitinomics profiling. Screening a diverse set of 100 cereblon (CRBN)-recruiting ligands on this platform leads to identification of a broad array of novel degraders and neosubstrates. Subsequent hit validation and structure-degradation relationship analyses guided by global proteomics reveal highly selective and potent phenyl glutarimide-based degraders targeting previously uncharacterized neosubstrates such as KDM4B, G3BP2 and VCL; none of which contain the classical CRBN β-hairpin degron. These findings underscore the power of unbiased high-throughput proteomics in MGD drug discovery and reveal a substantially expanded CRBN neosubstrate landscape beyond that defined by classical immunomodulatory imid drugs (IMiDs). Molecular glue degraders (MGD) offer a way to target undruggable proteins, but their discovery is challenging. Here, the authors develop a high-throughput proteomics platform for MGD drug discovery, revealing a much larger cereblon neosubstrate space than initially thought.

Drug resistance is a major challenge in cancer therapy, especially in the context of kinase inhibitors. While targeted protein degradation (TPD) was a distinct mode of action compared to inhibition-based therapeutic targeting, the potential value of TPD in drug-resistant cancer remains unclear. Here, we report the discovery of cereblon-recruiting molecular glue degraders (MGDs) targeting LCK, an oncogenic kinase in T-cell acute lymphoblastic leukemia (T-ALL). By high-throughput screening and medicinal chemistry optimization, we developed a series of MGDs that induced CRBN-dependent degradation of LCK as well as potent cytotoxicity in T-ALL in vitro. Structure-activity relationship analysis and ternary complex modeling revealed a non-canonical degron at the LCK-CRBN interface involving the G-loop, whose mutation disrupts this interaction. Unlike inhibitors and inhibitor-based PROTACs, these MGDs engage LCK in regions distal to the ATP binding site and thus their activities in T-ALL are not affected by gate-keeper LCK mutations that drive resistance to inhibitor-based therapeutics. Taken together, our data underscore the potential of LCK-targeting MGDs as a strategy to overcome kinase inhibitor resistance in T-ALL, highlighting a potentially generalizable strategy in cancer therapy.

Thyrsiferol is a marine natural product known to display cytotoxic activity against cancer cell lines. The total synthesis of a novel analogue of thyrsiferol (7,11-epi-thyrsiferol, 3-73) is described, it featuring a titaniumIII-mediated coupling reaction. The regioselective opening of epoxide 3-57 and stereoselective formation of compound 3-56 using Cp2TiCl constitute the key transformations for the successful completion of 3-73. The total synthesis of 7,11- epi-thyrsiferol proceeded in 32 steps with 17 steps for the longest linear sequence. Efforts toward the total synthesis of the natural product thyrsiferol are also discussed. Preliminary pharmacological studies indicated the novel analogue to inhibit cell division in the sea urchin assay at 11 μM concentration. In addition, the compound displayed a synergistic behavior with colchicine and it appears to be a substrate of multidrug resistance protein1 (MRP1).