FRTX-02是一种选择性和有效的DYRK1A抑制剂,可调节银屑病和特应性皮炎小鼠模型中的炎症途径

IF 4.7 Q2 IMMUNOLOGY Journal of Translational Autoimmunity Pub Date : 2023-01-01 DOI:10.1016/j.jtauto.2022.100185
Soochan Kim , Eunhwa Ko , Hwan Geun Choi , Daekwon Kim , Monica Luchi , Bernard Khor , Sunghwan Kim
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摘要

双特异性酪氨酸磷酸化调节激酶1a (DYRK1A)已被认为是一种通过调节T细胞极化来调节适应性免疫稳态的新型调节剂。因此,DYRK1A可能是自身免疫性疾病的潜在靶点。在这里,我们发现FRTX-02是一种新型化合物,表现出对DYRK1A的有效和选择性抑制。FRTX-02诱导T细胞系中DYRK1A底物NFAT的转录活性。相应的,FRTX-02促进体外CD4+极化为抗炎treg细胞,减少其极化为促炎Th1或Th17细胞。我们发现FRTX-02还可以通过负调控肥大细胞系中的MyD88/ IRAK4-NF -κB轴来限制先天免疫反应。最后,在银屑病和特应性皮炎小鼠模型中,口服和外用FRTX-02制剂均以剂量依赖的方式减少炎症和疾病生物标志物。这些结果支持进一步研究DYRK1A抑制剂,包括FRTX-02,作为慢性炎症和自身免疫性疾病的潜在治疗方法。
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FRTX-02, a selective and potent inhibitor of DYRK1A, modulates inflammatory pathways in mouse models of psoriasis and atopic dermatitis

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) has been proposed as a novel regulator of adaptive immune homeostasis through modulating T cell polarization. Thus, DYRK1A could present a potential target in autoimmune disorders. Here, we identify FRTX-02 as a novel compound exhibiting potent and selective inhibition of DYRK1A. FRTX-02 induced transcriptional activity of the DYRK1A substrate NFAT in T cell lines. Correspondingly, FRTX-02 promoted ex vivo CD4+ polarization into anti-inflammatory Tregs and reduced their polarization into pro-inflammatory Th1 or Th17 cells. We show that FRTX-02 could also limit innate immune responses through negative regulation of the MyD88/IRAK4–NF-κB axis in a mast cell line. Finally, in mouse models of psoriasis and atopic dermatitis, both oral and topical formulations of FRTX-02 reduced inflammation and disease biomarkers in a dose-dependent manner. These results support further studies of DYRK1A inhibitors, including FRTX-02, as potential therapies for chronic inflammatory and autoimmune conditions.

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来源期刊
Journal of Translational Autoimmunity
Journal of Translational Autoimmunity Medicine-Immunology and Allergy
CiteScore
7.80
自引率
2.60%
发文量
33
审稿时长
55 days
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