title: A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor β Subunit, Glycoprotein 130.
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.
authors.affiliation: Department of Drug Development, College of Medicine, Inha University, Incheon 400-712, Republic of Korea;
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea;
authors.forename: Jung Ho
authors.initials: JH
authors.lastname: Choi
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea;
authors.forename: Sung Yoon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea;
authors.forename: Yeon-Hwa
authors.initials: YH
authors.lastname: Park
authors.affiliation: Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea;
authors.forename: Kyung-Yeon
authors.initials: KY
authors.lastname: Park
authors.affiliation: Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea;
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Drug Development, College of Medicine, Inha University, Incheon 400-712, Republic of Korea;
authors.forename: Juyoung
authors.initials: J
authors.lastname: Kim
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea;
authors.forename: Veeraswamy
authors.initials: V
authors.lastname: Gajulapati
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea;
authors.forename: Ja-Il
authors.initials: JI
authors.lastname: Goo
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea;
authors.forename: Sarbjit
authors.initials: S
authors.lastname: Singh
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Goyang 410-820, Republic of Korea;
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea;
authors.forename: Young-Kook
authors.initials: YK
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea;
authors.forename: So Hee
authors.initials: SH
authors.lastname: Im
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea; and.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Department of Biochemistry, University of Kiel, Kiel 24098, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: 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.
authors.forename: Tae-Hwe
authors.initials: TH
authors.lastname: Heo
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; thhur92@catholic.ac.kr ychoi@korea.ac.kr.
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Choi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D023303:Oxazolidinones / Q000494:pharmacology*; D010195:Pancreatitis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D050822:Cytokine Receptor gp130; D015850:Interleukin-6; D053614:Janus Kinase 2; D023303:Oxazolidinones; D050796:STAT3 Transcription Factor; D054852:Small Molecule Libraries; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C494200:Il6st protein, mouse; C000600815:LMT-28; C494087:Stat3 protein, mouse; C507926:Jak2 protein, mouse