A novel small molecule inhibitor targeting gp130 (CCR3P.217)

Abstract

Abstract Interleukin-6 (IL-6) is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists we screened our in-house chemical library and identified a novel synthetic compound as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular targets of the compound were investigated. A reporter gene assay showed that the compound suppressed activation of signal transducer and activator of transcription-3 (STAT3) induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, the compound downregulated IL-6-stimulated phosphorylation of STAT3, gp130, and JAK2 protein in HepG2 cells and substantially inhibited IL-6-dependent TF-1 cell proliferation. The compound antagonized IL-6-induced TNF-α production in vivo, but did not affect IL-2-induced TNF-α production. In pathologic models, oral administration of the compound ameliorated collagen-induced arthritis and acute pancreatitis in mice. We subsequently demonstrated direct and specific interaction between the compound and gp130, which was measured by SPR analysis (KD = 7.4 μM) and was simulated by a docking study. Taken together, our data suggest that the compound is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130.