title: Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential.
abstract: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in a broad range of inflammatory and oncologic diseases. MIF is unique among cytokines in terms of its release profile and inflammatory role, notably as an endogenous counter-regulator of the anti-inflammatory effects of glucocorticoids. In addition, it exhibits a catalytic tautomerase activity amenable to the design of high affinity small molecule inhibitors. Although several classes of these compounds have been identified, biologic characterization of these molecules remains a topic of active investigation. In this study, we used in vitro LPS-driven assays to characterize representative molecules from several classes of MIF inhibitors. We determined that MIF inhibitors exhibit distinct profiles of anti-inflammatory activity, especially with regard to TNFα. We further investigated a molecule with relatively low anti-inflammatory activity, compound T-614 (also known as the anti-rheumatic drug iguratimod), and found that, in addition to exhibiting selective MIF inhibition in vitro and in vivo, iguratimod also has additive effects with glucocorticoids. Furthermore, we found that iguratimod synergizes with glucocorticoids in attenuating experimental autoimmune encephalitis, a model of multiple sclerosis. Our work identifies iguratimod as a valuable new candidate for drug repurposing to MIF-relevant diseases, including multiple sclerosis.
authors: From the Hofstra-Northwell School of Medicine, Hempstead, New York 11549, jbloom2@northwell.edu.|the Centers for Molecular Innovation.
authors: Joshua
authors: J
authors: Bloom
authors: From the Hofstra-Northwell School of Medicine, Hempstead, New York 11549.|Biomedical Sciences, and.
authors: Christine
authors: C
authors: Metz
authors: the Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249.
authors: Saisha
authors: S
authors: Nalawade
authors: the Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249.
authors: Julian
authors: J
authors: Casabar
authors: the Centers for Molecular Innovation.
authors: Kai Fan
authors: KF
authors: Cheng
authors: the Centers for Molecular Innovation.
authors: Mingzhu
authors: M
authors: He
authors: From the Hofstra-Northwell School of Medicine, Hempstead, New York 11549.|Immunology and Inflammation, and.
authors: Barbara
authors: B
authors: Sherry
authors: the Office of Technology Transfer, The Feinstein Institute for Medical Research, Manhasset, New York 11030, and.
authors: Thomas
authors: T
authors: Coleman
authors: the Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249.
authors: Thomas
authors: T
authors: Forsthuber
authors: From the Hofstra-Northwell School of Medicine, Hempstead, New York 11549, yalabed@northwell.edu.|the Centers for Molecular Innovation.
authors: Yousef
authors: Y
authors: Al-Abed
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002867:Chromones / Q000819:agonists / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D005938:Glucocorticoids / Q000819:agonists / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000819:agonists / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002867:Chromones; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C519076:iguratimod; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: MIF; drug discovery; drug screening; glucocorticoid; iguratimod; inflammation; substrate specificity