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Translating JAKs to Jakinibs

Massimo Gadina, Danielle A. Chisolm, Rachael L. Philips, Iain B. McInness, Paul S. Changelian and John J. O’Shea
J Immunol April 15, 2020, 204 (8) 2011-2020; DOI: https://doi.org/10.4049/jimmunol.1901477
Massimo Gadina
*Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
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Danielle A. Chisolm
†Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
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Rachael L. Philips
†Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
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Iain B. McInness
‡Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom; and
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Paul S. Changelian
§Aclaris Therapeutics, Inc., Wayne, PA 19087
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John J. O’Shea
†Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
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Abstract

The discovery of JAKs and STATs and their roles in cytokine and IFN action represented a significant basic advance and a new paradigm in cell signaling. This was quickly followed by discoveries pointing to their essential functions, including identification of JAK3 mutations as a cause of SCID. This and other findings predicted the use of therapeutically targeting JAKs as a new strategy for treating immune and inflammatory diseases. This now is a reality with seven approved jakinibs being used to treat multiple forms of arthritis, inflammatory bowel disease and myeloproliferative neoplasms, and numerous ongoing clinical trials in other settings. This story provides interesting insights into the process of translating basic discoveries and also reveals the need to return to basic work to fill gaps that now become apparent.

Footnotes

  • This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program.

  • Abbreviations used in this article:

    ATC
    Anatomical Therapeutic Chemical
    Btk
    Bruton tyrosine kinase
    EPO
    erythropoietin
    GVHD
    graft-versus-host disease
    IBD
    inflammatory bowel disease
    MPN
    myeloproliferative neoplasm
    RA
    rheumatoid arthritis
    SLE
    systemic lupus erythematosus
    TYK2
    tyrosine kinase 2
    UC
    ulcerative colitis.

  • Received December 16, 2019.
  • Accepted February 11, 2020.
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The Journal of Immunology: 204 (8)
The Journal of Immunology
Vol. 204, Issue 8
15 Apr 2020
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Translating JAKs to Jakinibs
Massimo Gadina, Danielle A. Chisolm, Rachael L. Philips, Iain B. McInness, Paul S. Changelian, John J. O’Shea
The Journal of Immunology April 15, 2020, 204 (8) 2011-2020; DOI: 10.4049/jimmunol.1901477

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Translating JAKs to Jakinibs
Massimo Gadina, Danielle A. Chisolm, Rachael L. Philips, Iain B. McInness, Paul S. Changelian, John J. O’Shea
The Journal of Immunology April 15, 2020, 204 (8) 2011-2020; DOI: 10.4049/jimmunol.1901477
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  • Article
    • Abstract
    • Introduction
    • Discovery of Janus kinases and their role in cytokine signaling
    • In vivo function of JAKs: Mendelian disorders, mutations, and knockouts
    • Jakinibs as a new class of drugs for autoimmune disease
    • Side effects of first-generation jakinibs
    • Next-generation, selective jakinibs
    • Conclusions
    • Disclosures
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