Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry
Open accessAbstract
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.
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Larger covalent DELs with approximately 100,000,000 members have been developed and used to identify acrylamide-based and epoxide-based BTK inhibitors with novel scaffolds.
“More recently, even larger covalent DELs (with approximately 100,000,000 members) have been developed and used to identify acrylamide-based and epoxide-based BTK inhibitors with novel scaffolds165.”
From Advances in covalent drug discovery (2022) · cites this paper as [165]
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Advances in covalent drug discovery
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- Authors
- Guilinger, J. P., Archna, A., Augustin, M., Bergmann, A., Centrella, P. A., Clark, M. A., Cuozzo, J. W., Däther, M., Guié, M.-A., Habeshian, S., Kiefersauer, R., Krapp, S., Lammens, A., Lercher, L., Liu, J., Liu, Y., Maskos, K., Mrosek, M., Pflügler, K., Siegert, M., Thomson, H. A., Tian, X., Zhang, Y., Konz Makino, D. L., & Keefe, A. D.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- Accent Therapeutics (United States) (US)
- Cyteir Therapeutics (United States) (US)
- Bruker (Germany) (DE)
- Nurix (United States) (US)
- Corresponding author
- Guilinger, John P.
- ORCID
- Venue
- Bioorganic & Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 42
- Pages
- 116223
- ISSN
- 0968-0896 (ISSN-L)
- OpenAlex
- W3161074835
- Cited by
- 49
- References
- 29
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 8 · 2023: 4 · 2022: 10 · 2021: 2
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Bioorganic & Medicinal Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- Bruton's tyrosine kinase, BTK inhibitors, DNA-encoded libraries, acrylamide, epoxides, kinase selectivity, drug discovery
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, DNA, Dose-Response Relationship, Drug, Humans, Structure-Activity Relationship, Molecular Structure, Crystallography, X-Ray, Protein Kinase Inhibitors, Small Molecule Libraries, Drug Discovery
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