2. Academic Validation
  3. A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor β Subunit, Glycoprotein 130

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

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; thhur92@catholic.ac.kr ychoi@korea.ac.kr.
  • 10 School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; thhur92@catholic.ac.kr ychoi@korea.ac.kr.
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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