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

BackgroundRheumatoid 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. MethodsStat3 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 then tested candidate Stat3-inhibiting activity in vitro by analyzing expression of IL-6, a Stat3 target, in compound-treated fibroblasts. We also analyzed expression of RANKL, a cytokine essential for osteoclastogenesis, in vitro. We then evaluated anti-arthritis effects of candidate compounds in vivo in collagen-induced arthritis model mice. Effects of the candidate compounds on inhibiting Stat3 phosphorylation and nuclear localization following IL-6 stimulation of fibroblasts were analyzed by an immune histocochemical analysis as well as western blotting.ResultsWe identified 15 as strong candidates as potential blockers of protein-protein interactions required for Stat3 dimerization using in silico screening from approximately 4.9 million small compounds. Four of the 15 significantly inhibited IL-6 as well as RANKL expression induced by IL-6. One compound, F0648-0027, significantly inhibited arthritis development without apparent adverse effects. F0648-0027 also significantly blocked Stat3 phosphorylation and nuclear localization following IL-6 stimulation of fibroblasts. ConclusionsThese data suggest that Stat3 is a target for RA, and that F0648-0027 could serve as a therapeutic reagent against the condition.