Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol
Open accessAbstract
The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.
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Covalent targeting of JAK3 Cys909 yields inhibitors selective for JAK3 over other JAK family members for autoimmune diseases.
“Covalent targeting of the non-conserved Cys909 of JAK3 has yielded inhibitors selective for JAK3 over other JAK family members for the treatment of autoimmune diseases77–81.”
From Advances in covalent drug discovery (2022) · cites this paper as [78]
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References 64 · Cited by 101
Research works printed but not linked: 1
- [39]39. Bricogne, G. ∙ Blanc, E. ∙ Brandl, M. ... BUSTER version 2.9.7.Global Phasing Ltd., Cambridge, UK, 2011 Google Scholar
- Authors
- Goedken, E. R., Argiriadi, M. A., Banach, D. L., Fiamengo, B. A., Foley, S. E., Frank, K. E., George, J. S., Harris, C. M., Hobson, A. D., Ihle, D. C., Marcotte, D., Merta, P. J., Michalak, M. E., Murdock, S. E., Tomlinson, M. J., & Voss, J. W.
- Corresponding author
- Goedken, Eric R.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 290
- Issue
- 8
- Pages
- 4573-4589
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4335200
- OpenAlex
- W2110025562
- Cited by
- 101
- References
- 64
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 8 · 2021: 11 · 2020: 8 · 2019: 13 · 2018: 10 · 2017: 14 · 2016: 8 · 2015: 5
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Argonne National Laboratory
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- JAK3, Janus kinase, JAK inhibitors, covalent inhibitors, irreversible kinase inhibitors, active site cysteine, kinase selectivity, ATP-competitive inhibitors, cytokine signaling, autoimmune disease, rheumatoid arthritis, inflammatory bowel disease, psoriasis
- MeSH terms
- Adenosine Triphosphate, Autoimmune Diseases, Cell Line, Humans, Catalytic Domain, Protein Kinase Inhibitors, Janus Kinase 3
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