ArticleCell chemical biology2023
Chemoproteomics-enabled discovery of a covalent molecular glue degrader targeting NF-κB.
Article in Cell chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 90 citations in OpenAlex.
- Systematic Targeting of Protein Complexes with Molecular COUPLrs.Cancer discovery · 2026Article
- Targeted protein degradation: bridging chemical biology and clinical translation.Acta pharmacologica Sinica · 2026Review
- Molecular glue degraders: Rational design, specificity engineering, and advanced delivery.Acta pharmaceutica Sinica. B · 2026Review
- Analysis of Confounding Factors in Reactive Cysteine Profiling Reveals Enhanced Chromatin-Protein Association via CDK7 Inhibition by THZ1.ACS chemical biology · 2026Article
- Targeting "undruggable" cancer proteins: pharmacological challenges and emerging strategies.Translational cancer research · 2026Review
- Neo-Cysteine Molecular Glues for Targeting Mutated SMAD4 Protein.Angewandte Chemie (International ed. in English) · 2026Article
- From Serendipity to Strategy: Rationalizing Molecular Glue Discovery and Proximity-Induced Pharmacology through Chemical Biology.Journal of the American Chemical Society · 2026Review
- Article
- Exploring Novel E3 Ligases and Neosubstrates for Molecular Glue Degraders and Therapeutic Applications in Cancer.Oncology research · 2026Review
- Ubiquitin-conjugating Enzymes in Cancer.International journal of biological sciences · 2026Review
- Covalent Ligand Electrophiles Are Differentially Activated by Proximity Effects Which Govern Latent Protein Reactivity.ACS central science · 2025Article
- Mechanisms that matter: unbiased cellular screening for degraders.npj drug discovery · 2025Review
- COOKIE-Pro: covalent inhibitor binding kinetics profiling on the proteome scale.Nature communications · 2025Article
- Unveiling the hidden interactome of CRBN molecular glues.Nature communications · 2025Article
- DCAF16-Based Covalent Degradative Handles for the Modular Design of Degraders.ACS central science · 2025Article
- Conditioned Generative Modeling of Molecular Glues: A Realistic AI Approach for Synthesizable Drug-like Molecules.Biomolecules · 2025Article
- Proteome-wide ligandability maps of drugs with diverse cysteine-reactive chemotypes.Nature communications · 2025Article
- Delineating cysteine-reactive compound modulation of cellular proteostasis processes.Nature chemical biology · 2025Article
- Covalent Proximity Inducers.Chemical reviews · 2025Review
- Template-assisted covalent modification underlies activity of covalent molecular glues.Nature chemical biology · 2024Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Targeted protein degradation has arisen as a powerful therapeutic modality for degrading disease targets. While proteolysis-targeting chimera (PROTAC) design is more modular, the discovery of molecular glue degraders has been more challenging. Here, we have coupled the phenotypic screening of a covalent ligand library with chemoproteomic approaches to rapidly discover a covalent molecular glue degrader and associated mechanisms. We have identified a cysteine-reactive covalent ligand EN450 that impairs leukemia cell viability in a NEDDylation and proteasome-dependent manner. Chemoproteomic profiling revealed covalent interaction of EN450 with an allosteric C111 in the E2 ubiquitin-conjugating enzyme UBE2D. Quantitative proteomic profiling revealed the degradation of the oncogenic transcription factor NFKB1 as a putative degradation target. Our study thus puts forth the discovery of a covalent molecular glue degrader that uniquely induced the proximity of an E2 with a transcription factor to induce its degradation in cancer cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.