title: A novel JAK-STAT inhibitor, 2-[(3-Carbamoyl-2-thienyl)amino]-2-oxoethyl(2,6-dichlorophenyl)acetate, suppresses helper T cell differentiation in vitro and collagen-induced arthritis in vivo.
abstract: Th17 cells, which have been implicated in autoimmune diseases including rheumatoid arthritis (RA), require the JAK-STAT3 pathway for their differentiation and functions. Recently, JAK inhibitors have been developed as a therapeutic drug for RA. However, the current JAK inhibitors are not optimized to STAT3 compared with other STATs. In this study, we found a new lead compound of a small molecule JAK-STAT inhibitor, 2-[(3-Carbamoyl-2-thienyl)amino]-2-oxoethyl (2,6-dichlorophenyl)acetate, which inhibits STAT3 as efficiently as other STATs. This compound, named JI069, was selected by STAT3 reporter assay in combination with an in silico docking model. JI069 inhibited gp130 signaling by inducing dissociation between gp130 and JAK1. In HEK293T cells and primary T cells, JI069 suppressed STAT3 activation as efficiently as other STATs, including STAT1, STAT5, and STAT6. JI069 effectively suppressed Th1, Th2, and Th17 differentiation while strongly promoted iTreg differentiation. JI069 suppressed symptoms of the collagen-induced arthritis (CIA) model in mice, and inhibited the cytokine production from T cells as well as the STAT3 phosphorylation of synovial cells. These data suggest that JI069 is a new type of JAK inhibitor which has potential for the treatment of immunological disorders.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Mayako
authors.initials: M
authors.lastname: Asakawa
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Sakai
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Saeki
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kanamori
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kotani
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: yoshimura@a6.keio.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000085:Acetates / Q000008:administration & dosage*; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D003094:Collagen; D016207:Cytokines / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D000085:Acetates; D016207:Cytokines; D050791:STAT Transcription Factors; D003094:Collagen
keywords: Cytokine signaling; Helper T cells; JAK1; STAT3; Th17