title: Mechanism of action and efficacy of RX-111, a thieno[2,3-c]pyridine derivative and small molecule inhibitor of protein interaction with glycosaminoglycans (SMIGs), in delayed-type hypersensitivity, TNBS-induced colitis and experimental autoimmune encephalomyelitis.
abstract: OBJECTIVE
  Elucidate the mechanism of action of the small molecule inhibitor of protein binding to glycosaminoglycans, RX-111 and assay its anti-inflammatory activity in animal models of inflammatory disease.
  
  
  METHODS
  The glycosaminoglycan, heparin, was used in the mechanism of action study of RX-111. Human T lymphocytes and umbilical vein endothelial cells were used to assay the in vitro activity of RX-111. Mouse and rat models of disease were used to assay the anti-inflammatory activity of RX-111 in vivo.
  
  
  METHODS
  Circular dichroism and UV/Vis absorption spectroscopy were used to study the binding of RX-111 to the glycosaminoglycan, heparin. T lymphocyte rolling on endothelial cells under shear flow was used to assay RX-111 activity in vitro. Delayed-type hypersensitivity (DTH) and tri-nitrobenzene sulfonic acid (TNBS)-induced colitis in mice and experimental autoimmune encephalomyelitis (EAE) in rats were used to assay anti-inflammatory activity of RX-111 in vivo.
  
  
  RESULTS
  RX-111 was shown to bind directly to heparin. It inhibited leukocyte rolling on endothelial cells under shear flow and reduced inflammation in the mouse model of DTH. RX-111 was efficacious in the mouse model of inflammatory bowel disease, TNBS-induced colitis and the rat model of multiple sclerosis, EAE.
  
  
  CONCLUSIONS
  RX-111 exercises its broad spectrum anti-inflammatory activity by a singular mechanism of action, inhibition of protein binding to the cell surface GAG, heparan sulfate. RX-111 and related thieno[2,3-c]pyridine derivatives are potential therapeutics for the treatment of inflammatory and autoimmune diseases.
authors.affiliation: Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel. nharris@braude.ac.il.|Ephraim Katzir Department of Biotechnology Engineering, ORT Braude Academic College of Engineering, 21982, Karmiel, Israel. nharris@braude.ac.il.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Harris
authors.affiliation: Institute of Animal Physiology, Slovak Academy of Sciences, 04001, Kosice, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Koppel
authors.affiliation: Biomolecular Self-Assembly Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Budapest, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Zsila
authors.affiliation: Institute of Animal Physiology, Slovak Academy of Sciences, 04001, Kosice, Slovakia.|Institute of Animal Physiology and Genetics of the ASCR, v. v. i., Rumburská 89, 277 21, Liběchov, Czech Republic.
authors.forename: Stefan
authors.initials: S
authors.lastname: Juhas
authors.affiliation: Institute of Animal Physiology, Slovak Academy of Sciences, 04001, Kosice, Slovakia.|GYN-FIV a.s., Záhradnícka 42, 821 085, Bratislava, Slovakia.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Il'kova
authors.affiliation: Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel.
authors.forename: Faina Yurgenzon
authors.initials: FY
authors.lastname: Kogan
authors.affiliation: Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Lahmy
authors.affiliation: Department of Immunology, Rappaport Institute, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Gizi
authors.initials: G
authors.lastname: Wildbaum
authors.affiliation: Department of Immunology, Rappaport Institute, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Nathan
authors.initials: N
authors.lastname: Karin
authors.affiliation: Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel.
authors.forename: Regina
authors.initials: R
authors.lastname: Zhuk
authors.affiliation: Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel. paul@gismotherapeutics.com.|GISMO Therapeutics Inc., A253 ASTECC-UK, Lexington, KY, 40506, USA. paul@gismotherapeutics.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregor
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology; D006497:Heparan Sulfate / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D036904:Leukocyte Rolling / Q000187:drug effects; D008297:Male; D008807:Mice, Inbred BALB C; D004676:Myelin Basic Protein / Q000276:immunology; D010081:Oxazolone; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D000893:Anti-Inflammatory Agents; D006497:Heparan Sulfate; D004676:Myelin Basic Protein; D010081:Oxazolone; D011725:Pyridines; D013876:Thiophenes; D014302:Trinitrobenzenesulfonic Acid; C000612946:RX-111
keywords: Autoimmune disease; Glycosaminoglycan; Heparan sulfate; Heparin binding protein; Inflammation; Small molecule drug