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

• Published in: Inflammation research Vol. 65; no. 4; pp. 285 - 294
• Main Authors: Harris, Nicholas, Koppel, Juraj, Zsila, Ferenc, Juhas, Stefan, Il’kova, Gabriela, Kogan, Faina Yurgenzon, Lahmy, Orly, Wildbaum, Gizi, Karin, Nathan, Zhuk, Regina, Gregor, Paul
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2016; Springer Nature B.V
• Subjects: Allergology; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Colitis - chemically induced; Colitis - drug therapy; Colitis - immunology; Dermatology; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Heparitin Sulfate - metabolism; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - immunology; Humans; Hypersensitivity, Delayed - chemically induced; Hypersensitivity, Delayed - drug therapy; Hypersensitivity, Delayed - immunology; Immunology; Leukocyte Rolling - drug effects; Male; Mice, Inbred BALB C; Myelin Basic Protein - immunology; Neurology; Original Research Paper; Oxazolone; Pharmacology/Toxicology; Pyridines - pharmacology; Pyridines - therapeutic use; Rats; Rats, Inbred Lew; Rheumatology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Thiophenes - pharmacology; Thiophenes - therapeutic use; Treatment Outcome; Trinitrobenzenesulfonic Acid; Heparan sulfate; Glycosaminoglycan; Heparin binding protein; Autoimmune disease; Inflammation; Small molecule drug
• ISSN: 1023-3830; 1420-908X
• DOI: 10.1007/s00011-016-0915-4

Objective and design 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. Materials 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.