title: A fluorinated analog of ISO-1 blocks the recognition and biological function of MIF and is orally efficacious in a murine model of colitis.
abstract: A promising therapeutic approach to diminish pathological inflammation is to inhibit the synthesis and/or biological activity of macrophage migration inhibitory factor (MIF). Prior studies have shown that intraperitoneal administration of small-molecule inhibitors targeting the catalytic pocket of MIF (e.g., ISO-1) elicits a therapeutic effect in mouse inflammation models. However, it remains to be elucidated whether these tautomerase activity inhibitors block the synthesis and/or biological activity of MIF. In this study, we investigated and compared the activity of representative MIF inhibitors from isoxazole series (fluorinated analog of ISO-1; ISO-F) and substituted quinoline series (compound 7E; 7E). Our results demonstrate that ISO-F is a more potent MIF inhibitor than 7E. Both ISO-F and 7E do not inhibit MIF synthesis but "bind-onto" MIF thereby blocking its recognition. However, in contrast to 7E, ISO-F docks well in the active site of MIF and also has a stronger binding affinity towards MIF. In line with these observations, ISO-F, but not 7E, robustly inhibits the biological function of MIF. Most importantly, ISO-F, when administered orally in a therapeutic regimen, significantly suppresses dextran sulphate sodium (DSS)-induced murine colitis. This study, which provides mechanistic insights into the anti-inflammatory efficacy of ISO-F, is the first documented report of in vivo anti-inflammatory efficacy of a MIF inhibitor upon oral administration. Moreover, the findings from this study reinforce the potential of catalytic site of MIF as a target for eliciting therapeutic effect in inflammatory disorders. Compounds (e.g., ISO-F) that block not only the recognition but also the biological function of MIF are potentially attractive for reducing pathological inflammation.
authors.affiliation: Department of Pharmacology, Piramal Life Sciences Limited, Mumbai, Maharashtra, India. nilesh.dagia@piramal.com
authors.forename: Nilesh M
authors.initials: NM
authors.lastname: Dagia
authors.forename: Divya V
authors.initials: DV
authors.lastname: Kamath
authors.forename: Pooja
authors.initials: P
authors.lastname: Bhatt
authors.forename: Ravindra D
authors.initials: RD
authors.lastname: Gupte
authors.forename: Shruta S
authors.initials: SS
authors.lastname: Dadarkar
authors.forename: Lyle
authors.initials: L
authors.lastname: Fonseca
authors.forename: Gautam
authors.initials: G
authors.lastname: Agarwal
authors.forename: Anshu
authors.initials: A
authors.lastname: Chetrapal-Kunwar
authors.forename: Sarala
authors.initials: S
authors.lastname: Balachandran
authors.forename: Shaila
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Julie
authors.initials: J
authors.lastname: Bose
authors.forename: Koteppa
authors.initials: K
authors.lastname: Pari
authors.forename: Chandrika
authors.initials: C
authors.lastname: B-Rao
authors.forename: Santosh S
authors.initials: SS
authors.lastname: Parkale
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Gadekar
authors.forename: Atish H
authors.initials: AH
authors.lastname: Rodge
authors.forename: Noopur
authors.initials: N
authors.lastname: Mandrekar
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.forename: Somesh
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy* / Q000503:physiopathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors; D007555:Isoxazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D000893:Anti-Inflammatory Agents; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D011804:Quinolines; D016264:Dextran Sulfate; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase