Tyrosine kinase 2 and Janus kinase‒signal transducer and activator of transcription signaling and inhibition in plaque psoriasis

Krueger, J. G., McInnes, I. B. and Blauvelt, A. (2022) Tyrosine kinase 2 and Janus kinase‒signal transducer and activator of transcription signaling and inhibition in plaque psoriasis. Journal of the American Academy of Dermatology, 86(1), pp. 148-157. (doi: 10.1016/j.jaad.2021.06.869) (PMID:34224773)

Abstract

Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a major role in intracellular cytokine signaling in inflammatory processes involved in psoriasis. Although Janus kinase (JAK) 1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe psoriasis, safety concerns persist and no JAK inhibitor has received regulatory approval to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis. Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and regulates signaling and functional responses downstream of the interleukin 12, interleukin 23, and type I interferon receptors. Deucravacitinib, which is an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and PF-06826647, which are topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews Janus kinase-signal transducer and activator of transcription and TYK2 signaling and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors.

• Item Type: Articles
• Keywords: Janus kinase signal transducer, TYK2, cytokine signaling, immune-mediated inflammatory disease, inhibition, plaque psoriasis.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McInnes, Professor Iain
• Authors: Krueger, J. G., McInnes, I. B., and Blauvelt, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Journal of the American Academy of Dermatology
• Publisher: Elsevier
• ISSN: 0190-9622
• ISSN (Online): 1097-6787
• Published Online: 02 July 2021
• Copyright Holders: Copyright © 2021 American Academy of Dermatology, Inc.
• First Published: First published in Journal of the American Academy of Dermatology 86(1): 148-157
• Publisher Policy: Reproduced under a Creative Commons License