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A novel highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2) can block inflammation- and autoimmune-related pathways

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العنوان: A novel highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2) can block inflammation- and autoimmune-related pathways
المؤلفون: Celia X.-J. Chen, Wei Zhang, Shulan Qu, Fucan Xia, Yidong Zhu, Bo Chen
المصدر: Cell Communication and Signaling, Vol 21, Iss 1, Pp 1-14 (2023)
بيانات النشر: BMC, 2023.
سنة النشر: 2023
المجموعة: LCC:Medicine
LCC:Cytology
مصطلحات موضوعية: TYK2, JAK, Cytokine pathway, Pseudokinase regulatory domain, Allosteric inhibitor, Psoriasis, Medicine, Cytology, QH573-671
الوصف: Abstract Background As a member of the Janus kinase (JAK) family, which includes JAK1, JAK2 and JAK3, tyrosine kinase 2 (TYK2) plays an important role in signal transduction and immune system regulation. Moreover, it is also involved in the development of many types of inflammatory and autoimmune diseases, such as psoriasis and systemic lupus erythematosus (SLE). TYK2 is an attractive therapeutic target, and selective inhibition of TYK2 over other JAK family members is critical for the development of TYK2 small molecule inhibitors. However, targeting the catalytic region of the TYK2 ATP-binding site is a major challenge due to the high structural homology between the catalytic regions of the JAK family proteins. Results In this study, we developed a novel small molecule inhibitor (QL-1200186) by targeting the pseudokinase regulatory domain (Janus homology 2, JH2) of the TYK2 protein. The binding sites of QL-1200186 were predicted and screened by molecular docking. The inhibitory effects on IFNα, IL-12 and IL-23 signaling were tested in cell lines, human peripheral blood cells and human whole blood. The pharmacokinetic (PK) and pharmacodynamic properties of QL-1200186 were verified in mice. QL-1200186 showed high affinity for TYK2 JH2 and had no apparent selectivity for the TYK2 and JAK homologous kinase domains; these effects were demonstrated using biochemical binding, signaling pathway transduction (JAK1/2/3) and off-target effect assays. More importantly, we revealed that QL-1200186 was functionally comparable and selectivity superior to two clinical-stage TYK2 inhibitors (BMS-986165 and NDI-034858) in vitro. In the PK studies, QL-1200186 exhibited excellent exposure, high bioavailability and low clearance rates in mice. Oral administration of QL-1200186 dose-dependently inhibited interferon-γ (IFNγ) production after interleukin-12 (IL-12) challenge and significantly ameliorated skin lesions in psoriatic mice. Conclusion These findings suggest that QL-1200186 is a highly selective and potent inhibitor of TYK2. QL-1200186 could be an appealing clinical drug candidate for the treatment of psoriasis and other autoimmune diseases. Video Abstract
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1478-811X
Relation: https://doaj.org/toc/1478-811X
DOI: 10.1186/s12964-023-01299-7
URL الوصول: https://doaj.org/article/71a93a7ec6444f7cb54f72fe8c4c1cb3
رقم الأكسشن: edsdoj.71a93a7ec6444f7cb54f72fe8c4c1cb3
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:1478811X
DOI:10.1186/s12964-023-01299-7