Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol

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 t...

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Bibliographic Details
Published in:The Journal of biological chemistry 2015-02, Vol.290 (8), p.4573-4589
Main Authors: Goedken, Eric R., Argiriadi, Maria A., Banach, David L., Fiamengo, Bryan A., Foley, Sage E., Frank, Kristine E., George, Jonathan S., Harris, Christopher M., Hobson, Adrian D., Ihle, David C., Marcotte, Douglas, Merta, Philip J., Michalak, Mark E., Murdock, Sara E., Tomlinson, Medha J., Voss, Jeffrey W.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Adenosine Triphosphate - analogs & derivatives
Adenosine Triphosphate - chemistry
Adenosine Triphosphate - pharmacology
Autoimmune Diseases - drug therapy
Autoimmune Diseases - enzymology
Autoimmune Diseases - genetics
BASIC BIOLOGICAL SCIENCES
Catalytic Domain
Cell Line
Covalent Inhibitor
Cytokine
Drug Discovery
Enzyme Inhibitor
Enzyme Kinetics
Enzymology
Humans
Jak3
Janus Kinase (JAK)
Janus Kinase 3 - antagonists & inhibitors
Janus Kinase 3 - chemistry
Janus Kinase 3 - genetics
Janus Kinase 3 - metabolism
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Tyrosine Kinase
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Summary: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. Background: Janus kinase 3 (Jak3) inhibitors hold promise for treatment of autoimmunity, but developing selective inhibitors is challenging. Results: We designed Jak3 inhibitors that avoid inhibition of the other JAKs. Conclusion: Our inhibitors possess high selectivity against other kinases and can potently inhibit Jak3 activity in cell-based assays. Significance: This class of irreversible inhibitors may be useful as selective agents of Jak3 inhibition.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.595181