ArticleDrug design, development and therapy2024
Evaluation of a Covalent Library of Diverse Warheads (CovLib) Binding to JNK3, USP7, or p53.
Article in Drug design, development and therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Covalent drug rescue of multiple p53 mutants by stabilizing vinyl sulfone fragments hints to a specific refolding mechanism for R282W.Protein science : a publication of the Protein Society · 2026Article
- Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs.Nature chemical biology · 2026Article
- False Friends in Fluorescence - Simple HPLC Evaluation of False Positive Fragment Hits in a DiFMUP Assay for Protein Tyrosine Phosphatase 1B.Drug design, development and therapy · 2026Article
- Characterization of the Second-Generation Covalent Fragment Library (CovLib Gen2): Thiol Reactivity Profiling and p53-Y220C Rescue.Drug design, development and therapy · 2026Article
- Advances in JNK inhibitor development: therapeutic prospects in neurodegenerative diseases and fibrosis.Archives of pharmacal research · 2025Review
- Discovery of RNA-Reactive Small Molecules Guides the Design of Electrophilic Modules for RNA-Specific Covalent Binders.Journal of the American Chemical Society · 2025Article
- Design, Synthesis, and Molecular Evaluation of SArchiv der Pharmazie · 2025Article
- Mechanistic Insights of a p53-Targeting Small Molecule.ACS pharmacology & translational science · 2025Article
- SDrug design, development and therapy · 2025Article
- Screening of Covalent Kinase Inhibitors Yields Hits for Cysteine Protease USP7 / HAUSP.Drug design, development and therapy · 2025Article
- Covalent Fragments Acting as Tyrosine Mimics for Mutant p53-Y220C Rescue by Nucleophilic Aromatic Substitution.ACS pharmacology & translational science · 2024Article
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10 authors.
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Abstract
Purpose: Over the last few years, covalent fragment-based drug discovery has gained significant importance. Thus, striving for more warhead diversity, we conceived a library consisting of 20 covalently reacting compounds. Our covalent fragment library (CovLib) contains four different warhead classes, including five α-cyanoacacrylamides/acrylates (CA), three epoxides (EO), four vinyl sulfones (VS), and eight electron-deficient heteroarenes with a leaving group (S Methods: After predicting the theoretical solubility of the fragments by LogP and LogS during the selection process, we determined their experimental solubility using a turbidimetric solubility assay. The reactivities of the different compounds were measured in a high-throughput 5,5'-dithiobis-(2-nitrobenzoic acid) DTNB assay, followed by a (glutathione) GSH stability assay. We employed the CovLib in a (differential scanning fluorimetry) DSF-based screening against different targets: c-Jun N-terminal kinase 3 (JNK3), ubiquitin-specific protease 7 (USP7), and the tumor suppressor p53. Finally, the covalent binding was confirmed by intact protein mass spectrometry (MS). Results: In general, the purchased fragments turned out to be sufficiently soluble. Additionally, they covered a broad spectrum of reactivity. All investigated α-cyanoacrylamides/acrylates and all structurally confirmed epoxides turned out to be less reactive compounds, possibly due to steric hindrance and reversibility (for α-cyanoacrylamides/acrylates). The S Conclusion: The screening and target evaluation of the CovLib revealed first interesting hits. The highly cysteine-reactive fragments VS004, SN001, SN006, and SN007 covalently modify several target proteins and showed distinct shifts in the melting temperatures up to +5.1 °C and -9.1 °C.
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