The Stat3 inhibitor F0648-0027 is a potential therapeutic against rheumatoid arthritis

Yosuke Kaneko, Shin ichiro Ozawa, Yuiko Sato, Tami Kobayashi, Tatsuaki Matsumoto, Kana Miyamoto, Shu Kobayashi, Kengo Harato, Shuichi Hirono, Morio Matsumoto, Masaya Nakamura, Yasuo Niki, Takeshi Miyamoto

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)133-140
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume636
DOIs
Publication statusPublished - 2022 Dec 25

Keywords

  • In silico screening
  • Rheumatoid arthritis (RA)
  • Signal transducer and activator of transcription 3 (Stat3)

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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