A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor β Subunit, Glycoprotein 130

  • J Immunol. 2015 Jul 1;195(1):237-45. doi: 10.4049/jimmunol.1402908.
Soon-Sun Hong  1 ,  Jung Ho Choi  2 ,  Sung Yoon Lee  3 ,  Yeon-Hwa Park  4 ,  Kyung-Yeon Park  4 ,  Joo Young Lee  4 ,  Juyoung Kim  1 ,  Veeraswamy Gajulapati  3 ,  Ja-Il Goo  3 ,  Sarbjit Singh  3 ,  Kyeong Lee  5 ,  Young-Kook Kim  2 ,  So Hee Im  6 ,  Sung-Hoon Ahn  7 ,  Stefan Rose-John  8 ,  Tae-Hwe Heo  9 ,  Yongseok Choi  10
Affiliations
  • 1. Department of Drug Development, College of Medicine, Inha University, Incheon 400-712, Republic of Korea;
  • 2. Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea;
  • 3. School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea;
  • 4. Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea;
  • 5. College of Pharmacy, Dongguk University-Seoul, Goyang 410-820, Republic of Korea;
  • 6. College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea;
  • 7. College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea; and.
  • 8. Department of Biochemistry, University of Kiel, Kiel 24098, Germany.
  • 9. Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea; [email protected] [email protected].
  • 10. School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; [email protected] [email protected].
PMID: 26026064 DOI: 10.4049/jimmunol.1402908
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 identified LMT-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.

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