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TYK2: an emerging therapeutic target in rheumatic disease

Nature Reviews Rheumatology volume 20, pages 232–240 (2024)Cite this article

Subjects

Abstract

Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family of intracellular signalling molecules. By participating in signalling pathways downstream of type I interferons, IL-12, IL-23 and IL-10, TYK2 elicits a distinct set of immune events to JAK1, JAK2 and JAK3. TYK2 polymorphisms have been associated with susceptibility to various rheumatic diseases including systemic lupus erythematosus and dermatomyositis. In vitro and animal studies substantiate these findings, highlighting a role for TYK2 in diseases currently managed by antagonists of cytokines that signal through TYK2. Various inhibitors of TYK2 have now been studied in human disease, and one of these inhibitors, deucravacitinib, has now been approved for the treatment of psoriasis. Phase II trials of deucravacitinib have also reported positive results in the treatment of psoriatic arthritis and systemic lupus erythematosus, with a preliminary safety profile that seems to differ from that of the JAK1, JAK2 and JAK3 inhibitors. Two other inhibitors of TYK2, brepocitinib and ropsacitinib, are also in earlier stages of clinical trials. Overall, TYK2 inhibitors hold promise for the treatment of a distinct spectrum of autoimmune diseases and could potentially have a safety profile that differs from other JAK inhibitors.

Key points

  • Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in signalling downstream of a distinct set of cytokines, including IL-12, IL-23, type I interferons and IL-10.

  • TYK2 has a potential role in diseases in which these cytokines are pathogenic; given its limited cytokine profile, inhibitors of TYK2 could have a different safety profile from other JAK inhibitors.

  • The selective TYK2 inhibitor deucravacitinib has a unique mode of action that involves allosteric inhibition of TYK2 via binding to a pseudokinase domain.

  • Other known inhibitors of TYK2, including brepocitinib and ropsacitinib, bind to the kinase domain of TYK2, and have inhibitory activity against other JAK kinases.

  • Phase III clinical trials of deucravacitinib have resulted in its approval for the treatment of plaque psoriasis, and phase II trials in psoriatic arthritis and systemic lupus erythematosus were positive.

  • Preliminary safety data to date suggest that deucravacitinib has a distinct safety profile compared with other JAK inhibitors.

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Fig. 1: Cytokine signalling through TYK2 and other JAKs.
Fig. 2: Potential indications for TYK2 blockade.

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Authors and Affiliations

  1. Centre for Inflammatory Diseases, Monash University, and Department of Rheumatology, Monash Health, Clayton, Victoria, Australia

    Eric Morand

  2. Department of Medicine, Division of Rheumatology and Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Joseph F. Merola

  3. The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan

    Yoshiya Tanaka

  4. Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Division of Rheumatology University of Toronto, Toronto, Ontario, Canada

    Dafna Gladman

  5. Metroplex Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Roy Fleischmann

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Correspondence to Eric Morand.

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R.F. declares that he has acted as a consultant for AbbVie, Amgen, Atomwise, BMS, Galvani, Galapagos, Gilead, GSK, Immunovant, Janssen, Eli Lilly. Novartis, Pfizer, UCB and Vyne; serves on the data safety monitoring boards for Celltrion, EMDSerano and Kiniksa; and has received clinical trial grants from AbbVie, Arthrosi, Biogen, BMS, Eli Lilly, Flexion, Galvani, Genentech, Gilead, GSK, Horizon, Janssen, Novartis, Oletec, Priovant, Scipher, Selecta, UCB and Viela. Y.T. declares that he has received speaking fees and/or honoraria from AbbVie, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers, Chugai, Daiichi-Sankyo, Eli Lilly, Eisai, Gilead, GlaxoSmithKline, Mitsubishi-Tanabe and Pfizer; and research grants from Asahi-Kasei, AbbVie, Behringer-Ingelheim, Chugai, Daiichi-Sankyo, Eisai and Takeda. D.G. declares that she has received grant support from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer and UCB; and consulting fees from AbbVie, Amgen, BMS, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer and UCB. E.M. declares that he has received research grants from AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, Takeda and UCB; and advisory and/or honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, GSK, Gilead, Novartis, Takeda and Zenas. J.F.M. declares that he has acted as a consultant for AbbVie, Biogen, Celgene, Dermavant, Eli Lilly, Janssen, Leo Pharma, Novartis, Pfizer and UCB.

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Morand, E., Merola, J.F., Tanaka, Y. et al. TYK2: an emerging therapeutic target in rheumatic disease. Nat Rev Rheumatol 20, 232–240 (2024). https://doi.org/10.1038/s41584-024-01093-w

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