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  • The Stat3 inhibitor F0648-0...
    Kaneko, Yosuke; Ozawa, Shin-ichiro; Sato, Yuiko; Kobayashi, Tami; Matsumoto, Tatsuaki; Miyamoto, Kana; Kobayashi, Shu; Harato, Kengo; Hirono, Shuichi; Matsumoto, Morio; Nakamura, Masaya; Niki, Yasuo; Miyamoto, Takeshi

    Biochemical and biophysical research communications, 12/2022, Volume: 636, Issue: Pt 2
    Journal Article

    Rheumatoid arthritis (RA) is a disease characterized by chronic joint inflammation, pain and joint destruction, leading to alteration in activities of daily living, yet pathological mechanisms underlying the condition are not fully clarified. To date, various therapeutic agents have been developed as RA therapy including DMARDs and/or biological agents that target inflammatory cytokines or inhibit JAK. Here we asked whether inhibiting signal transducer and activator of transcription 3 (Stat3) activity would antagonize RA. Stat3 forms dimers when activated and undergoes nuclear translocalization; thus we screened approximately 4.9 million small compounds as potential blockers of protein-protein interactions required for Stat3 dimerization using in silico screening. We identified 15 as strong candidates as potential blockers of protein-protein interactions required for Stat3 dimerization using in silico screening from those compounds. Four of the 15 significantly inhibited expression of IL-6 and RANKL, both of which are direct targets of Stat3, induced by IL-6. Among four, one compound, F0648-0027, significantly inhibited arthritis development without apparent adverse effects in vivo in collagen-induced arthritis model mice. F0648-0027 also significantly blocked Stat3 phosphorylation and nuclear localization following IL-6 stimulation of fibroblasts. These data suggest that Stat3 is a target for collagen-induced arthritis in mice, and that F0648-0027 could serve as a therapeutic reagent against comparable conditions in humans. •Stat3 inhibiting compounds were screened from approximately 4.9 million compounds.•F0648-0027 was isolated as the most effective Stat3 inhibitor in vitro and in vivo.•Phosphorylation of Stat3 by IL-6 stimulation was inhibited by F0648-0027.•Nuclear translocation of Stat3 by IL-6 stimulation was inhibited by F0648-0027.•Arthritis score in RA mouse models was significantly inhibited by F0648-0027.