A Specific and Covalent JNK‐1 Ligand Selected from an Encoded Self‐Assembling Chemical Library
Open accessAbstract
We describe the construction of a DNA‐encoded chemical library comprising 148 135 members, generated through the self‐assembly of two sub‐libraries, containing 265 and 559 members, respectively. The library was designed to contain building blocks potentially capable of forming covalent interactions with target proteins. Selections performed with JNK1, a kinase containing a conserved cysteine residue close to the ATP binding site, revealed the preferential enrichment of a 2‐phenoxynicotinic acid moiety (building block A82) and a 4‐(3,4‐difluorophenyl)‐4‐oxobut‐2‐enoic acid moiety (building block B272). When the two compounds were joined by a short PEG linker, the resulting bidentate binder (A82‐L‐B272) was able to covalently modify JNK1 in the presence of a large molar excess of glutathione (0.5 m m), used to simulate intracellular reducing conditions. By contrast, derivatives of the individual building blocks were not able to covalently modify JNK1 in the same experimental conditions. The A82‐L‐B272 ligand was selective over related kinases (BTK and GAK), which also contain targetable cysteine residues in the vicinity of the active site.
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Cysteine-targeted DNA-encoded or protein-nucleic acid-encoded libraries have identified covalent ligands for bromodomains including PCAF and BRD4, as well as for JNK1, MEK2, and HER2.
“over the past 5 years, cysteine-targeted DNA-encoded or protein–nucleic acid-encoded libraries have been used to identify covalent ligands for bromodomains, including PCAF and BRD4, as well as for JNK1, MEK2 and HER2 (refs.160–162).”
From Advances in covalent drug discovery (2022) · cites this paper as [160]
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- Authors
- Zimmermann, G., Rieder, U., Bajic, D., Vanetti, S., Chaikuad, A., Knapp, S., Scheuermann, J., Mattarella, M., & Neri, D.
- Affiliations
- ETH Zurich (CH)
- Philochem (Switzerland) (CH)
- Goethe University Frankfurt (DE)
- Corresponding author
- Mattarella, Martin
- Neri, Dario
- Venue
- Chemistry – A European Journal
- Publisher
- Wiley
- Published
- 2017-05-30
- Volume
- 23
- Issue
- 34
- Pages
- 8152-8155
- ISSN
- 0947-6539 (ISSN-L)
- 1521-3765
- PMC
- PMC5557334
- OpenAlex
- W2613253068
- Cited by
- 77
- References
- 52
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 10 · 2023: 4 · 2022: 12 · 2021: 8 · 2020: 11 · 2019: 6 · 2018: 10 · 2017: 1
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Chemistry - A European Journal (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, other-oa)
- ETH Zürich Research Collection
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII2_160699, 310030B_163479/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
- Keywords
- JNK1, covalent kinase inhibitors, DNA-encoded libraries, PEG linker, glutathione, kinase selectivity, Bruton's tyrosine kinase, GAK
- MeSH terms
- Ligands, Gene Library, Mitogen-Activated Protein Kinase 8, Small Molecule Libraries
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