Soochan Kim , Eunhwa Ko , Hwan Geun Choi , Daekwon Kim , Monica Luchi , Bernard Khor , Sunghwan Kim
{"title":"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","authors":"Soochan Kim , Eunhwa Ko , Hwan Geun Choi , Daekwon Kim , Monica Luchi , Bernard Khor , Sunghwan Kim","doi":"10.1016/j.jtauto.2022.100185","DOIUrl":null,"url":null,"abstract":"<div><p>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<sup>+</sup> 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.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":null,"pages":null},"PeriodicalIF":4.7000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/12/55/main.PMC9841288.pdf","citationCount":"0","resultStr":"{\"title\":\"FRTX-02, a selective and potent inhibitor of DYRK1A, modulates inflammatory pathways in mouse models of psoriasis and atopic dermatitis\",\"authors\":\"Soochan Kim , Eunhwa Ko , Hwan Geun Choi , Daekwon Kim , Monica Luchi , Bernard Khor , Sunghwan Kim\",\"doi\":\"10.1016/j.jtauto.2022.100185\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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<sup>+</sup> 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.</p></div>\",\"PeriodicalId\":36425,\"journal\":{\"name\":\"Journal of Translational Autoimmunity\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/12/55/main.PMC9841288.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Translational Autoimmunity\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2589909022000466\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Translational Autoimmunity","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2589909022000466","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
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.