Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry
| Autor: | Sevan Habeshian, Lukas Lercher, Ying Zhang, John W. Cuozzo, Yanbin Liu, Xia Tian, Martin Augustin, Andreas Bergmann, Stephan Krapp, Michael Mrosek, Alfred Lammens, Paolo A. Centrella, Archna Archna, Maike Däther, Marie-Aude Guié, Debora L. Konz Makino, Klaus Pflügler, Reiner Kiefersauer, Julie Liu, Klaus Maskos, John P. Guilinger, Anthony D. Keefe, Heather A. Thomson, Matthew A. Clark, Markus Siegert |
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| Rok vydání: | 2021 |
| Předmět: |
kinase inhibitor
Clinical Biochemistry Pharmaceutical Science dna-encoded chemical libraries (decl) Crystallography X-Ray 01 natural sciences Biochemistry Small Molecule Libraries Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Agammaglobulinaemia Tyrosine Kinase Humans Bruton's tyrosine kinase Protein Kinase Inhibitors Molecular Biology Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Drug discovery Chemistry Oligonucleotide Organic Chemistry tryptoline DNA cell Combinatorial chemistry Small molecule 0104 chemical sciences covalent irreversible inhibitor 010404 medicinal & biomolecular chemistry Covalent bond Electrophile epoxide biology.protein Molecular Medicine Tyrosine kinase |
| Zdroj: | Bioorganic & Medicinal Chemistry. 42:116223 |
| ISSN: | 0968-0896 |
| Popis: | Libraries of DNA-Encoded small molecules created using combinatorial chemistry and synthetic oligonucleotides are being applied to drug discovery projects across the pharmaceutical industry. The majority of reported projects describe the discovery of reversible, i.e. non-covalent, target modulators. We synthesized multiple DNA-encoded chemical libraries terminated in electrophiles and then used them to discover covalent irreversible inhibitors and report the successful discovery of acrylamide- and epoxide-terminated Bruton's Tyrosine Kinase (BTK) inhibitors. We also demonstrate their selectivity, potency and covalent cysteine engagement using a range of techniques including X-ray crystallography, thermal transition shift assay, reporter displacement assay and intact protein complex mass spectrometry. The epoxide BTK inhibitors described here are the first ever reported to utilize this electrophile for this target. |
| Databáze: | OpenAIRE |
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