title: Macrophage migration inhibitory factor (MIF) enzymatic activity and lung cancer.
abstract: The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity, which contributes to the biological functional activity of MIF. In this study, we investigated the effects of blocking the hydrophobic active site of the tautomerase activity of MIF in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumor growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif (P1G)). Primary tumor growth was significantly attenuated in both Mif-KO and Mif (P1G) mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for the tautomerase enzymatic active site of MIF. From primary and secondary screens, the inhibitor SCD-19 was identified, which significantly attenuated the tautomerase enzymatic activity of MIF in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumor inoculation, was found to significantly reduce primary tumor volume by 90% (p < 0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumor was palpable (at d 7 after tumor inoculation) and, again, treatment was found to significantly reduce tumor volume by 81% (p < 0.001) compared with the control treatment. In this report, we identify a novel inhibitor that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems.
authors.affiliation: Conway Institute for Biomolecular and Biomedical Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Leona
authors.initials: L
authors.lastname: Mawhinney
authors.affiliation: Conway Institute for Biomolecular and Biomedical Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Armstrong
authors.affiliation: Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Ciaran
authors.initials: C
authors.lastname: O' Reilly
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.affiliation: Department of Internal Medicine 1, University Hospital Cologne, Centre for Integrated Oncology Köln-Bonn, Cologne, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.affiliation: Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Darren
authors.initials: D
authors.lastname: Fayne
authors.affiliation: Conway Institute for Biomolecular and Biomedical Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Keane
authors.affiliation: Conway Institute for Biomolecular and Biomedical Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Aisling
authors.initials: A
authors.lastname: Tynan
authors.affiliation: Conway Institute for Biomolecular and Biomedical Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Lewena
authors.initials: L
authors.lastname: Maher
authors.affiliation: Conway Institute for Biomolecular and Biomedical Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Gordon
authors.initials: G
authors.lastname: Cooke
authors.affiliation: Division of Health Sciences, University of South Australia, Adelaide, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Lloyd
authors.affiliation: Conway Institute for Biomolecular and Biomedical Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Helen
authors.initials: H
authors.lastname: Conroy
authors.affiliation: Conway Institute for Biomolecular and Biomedical Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Seamas C
authors.initials: SC
authors.lastname: Donnelly
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D049934:Isocoumarins / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C000603036:3-(2'-methylphenyl)isocoumarin; D000970:Antineoplastic Agents; D049934:Isocoumarins; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D014409:Tumor Necrosis Factor-alpha; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse; D015232:Dinoprostone
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