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JAK inhibitor selectivity: new opportunities, better drugs?

Nature Reviews Rheumatology volume 20, pages 649–665 (2024)Cite this article

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Abstract

Cytokines function as communication tools of the immune system, serving critical functions in many biological responses and shaping the immune response. When cytokine production or their biological activity goes awry, the homeostatic balance of the immune response is altered, leading to the development of several pathologies such as autoimmune and inflammatory disorders. Cytokines bind to specific receptors on cells, triggering the activation of intracellular enzymes known as Janus kinases (JAKs). The JAK family comprises four members, JAK1, JAK2, JAK3 and tyrosine kinase 2, which are critical for intracellular cytokine signalling. Since the mid-2010s multiple JAK inhibitors have been approved for inflammatory and haematological indications. Currently, approved JAK inhibitors have demonstrated clinical efficacy; however, improved selectivity for specific JAKs is likely to enhance safety profiles, and different strategies have been used to accomplish enhanced JAK selectivity. In this update, we discuss the background of JAK inhibitors, current approved indications and adverse effects, along with new developments in this field. We address the issue of JAK selectivity and its relevance in terms of efficacy, and describe new modalities of JAK targeting, as well as new aspects of JAK inhibitor action.

Key points

  • Januse kinase (JAK) inhibitors show equivalent or superior efficacy compared with biologic DMARDs in several autoimmune and inflammatory diseases.

  • The use of JAK inhibitors has been hampered by adverse events, which could be linked to the JAKs that are blocked.

  • Assessment of individual JAK inhibitor selectivity is still a matter of debate, as different assays can yield different results.

  • Selective JAK inhibitors are generally equally effective, but improved, long-term safety has not been fully established.

  • Tissue-targeted JAK inhibitors could circumvent the problem of adverse effects resulting from systemic administration.

  • Alternative strategies for JAK inhibition with small interfering RNAs or metabolite derivatives constitute an exciting area of development.

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Fig. 1: Function and inhibition of Janus kinases.
Fig. 2: Structure of JAK and inhibitor target sites.
Fig. 3: Timeline of JAK inhibitor development.

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Authors and Affiliations

  1. Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

    Anniina Virtanen & Olli Silvennoinen

  2. Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland

    Anniina Virtanen & Olli Silvennoinen

  3. Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari-Reumatologia, Sapienza Universitá di Roma, Rome, Italy

    Francesca Romana Spinelli

  4. Inflammation and Immunology, Pfizer, Cambridge, MA, USA

    Jean Baptiste Telliez

  5. Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

    John J. O’Shea

  6. Fimlab laboratories, Tampere, Finland

    Olli Silvennoinen

  7. Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

    Massimo Gadina

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O.S. is a scientific advisory board member and co-founder of Ajax Therapeutics Inc. J.B.T. is an employee of Pfizer Inc.

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Virtanen, A., Spinelli, F.R., Telliez, J.B. et al. JAK inhibitor selectivity: new opportunities, better drugs?. Nat Rev Rheumatol 20, 649–665 (2024). https://doi.org/10.1038/s41584-024-01153-1

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