ArticleCell communication and signaling : CCS2023
A novel highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2) can block inflammation- and autoimmune-related pathways.
Article in Cell communication and signaling : CCS, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 13 citations in OpenAlex.
- Review
- The JAK-STAT pathway in allergic diseases: from pathogenesis to targeted therapy.Biomarker research · 2026Review
- PocketMaster provides a flexible and automated tool for analyzing, clustering, and visualizing structural diversity in protein pockets.Scientific reports · 2026Article
- Probing Allosteric Kinase Modulators as Next Game-Changers in Fighting Neurodegeneration.Journal of medicinal chemistry · 2026Review
- From Convenience to Clinical Efficacy: Selective TYK2 Inhibition in Psoriasis and the Evolving Role of Next-Generation Oral Targeted Therapies.Pharmaceutics · 2026Review
- [A real world study on the effectiveness and safety of deu-cravacitinib in the treatment of moderate-to-severe plaque psoriasis in China].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2025Article
- Molecular and cellular mechanisms of itch sensation and the anti-itch drug targets.Acta pharmacologica Sinica · 2025Review
- Deep learning-guided discovery of selective JAK2-JH2 allosteric inhibitors: integration of MLP predictive modeling, BREED-based library design, and computational validation.Frontiers in chemistry · 2025Article
- Immune-mediated renal injury in diabetic kidney disease: from mechanisms to therapy.Frontiers in immunology · 2025Review
- Corneal application of SOCS1/3 peptides for the treatment of eye diseases mediated by inflammation and oxidative stress.Frontiers in immunology · 2024Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAs 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.
resultsIn 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.
conclusionThese 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.
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