A novel small-molecule inhibitor targeting the IL-6 receptor β subunit, glycoprotein 130

Soon Sun Hong, Jung Ho Choi, Sung Yoon Lee, Yeon Hwa Park, Kyung Yeon Park, Joo Young Lee, Juyoung Kim, Veeraswamy Gajulapati, Ja Il Goo, Sarbjit Singh, Kyeong Lee, Young Kook Kim, So Hee Im, Sung Hoon Ahn, Stefan Rose-John, Tae Hwe Heo, Yongseok Choi

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28 Citations (Scopus)

Abstract

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 identifiedLMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6-stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6-dependent TF-1 cell proliferation. LMT-28 antagonized IL-6-induced TNF-α production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL-6, IL-6Rα, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6Rα complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130.

Original languageEnglish
Pages (from-to)237-245
Number of pages9
JournalJournal of Immunology
Volume195
Issue number1
DOIs
Publication statusPublished - 2015 Jul 1

ASJC Scopus subject areas

  • Immunology

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    Hong, S. S., Choi, J. H., Lee, S. Y., Park, Y. H., Park, K. Y., Lee, J. Y., Kim, J., Gajulapati, V., Goo, J. I., Singh, S., Lee, K., Kim, Y. K., Im, S. H., Ahn, S. H., Rose-John, S., Heo, T. H., & Choi, Y. (2015). A novel small-molecule inhibitor targeting the IL-6 receptor β subunit, glycoprotein 130. Journal of Immunology, 195(1), 237-245. https://doi.org/10.4049/jimmunol.1402908