title: ISO-66, a novel inhibitor of macrophage migration, shows efficacy in melanoma and colon cancer models.
abstract: Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine, which possesses a contributing role in cancer progression and metastasis and, thus, is now considered a promising anticancer drug target. Many MIF-inactivating strategies have proven successful in delaying cancer growth. Here, we report on the synthesis of ISO-66, a novel, highly stable, small-molecule MIF inhibitor, an analog of ISO-1 with improved characteristics. The MIF:ISO-66 co-crystal structure demonstrated that ISO-66 ligates the tautomerase active site of MIF, which has previously been shown to play an important role in its biological functions. In vitro, ISO-66 enhanced specific and non-specific anticancer immune responses, whereas prolonged administration of ISO-66 in mice with established syngeneic melanoma or colon cancer was non-toxic and resulted in a significant decrease in tumor burden. Subsequent ex vivo analysis of mouse splenocytes revealed that the observed decrease in tumor growth rates was likely mediated by the selective in vivo expansion of antitumor-reactive effector cells induced by ISO-66. Compared to other MIF-inactivating strategies employed in vivo, the anticancer activity of ISO-66 is demonstrated to be of equal or better efficacy. Our findings suggest that targeting MIF, via highly specific and stable compounds, such as ISO-66, may be effective for cancer treatment and stimulation of anticancer immune responses.
authors: Department of Animal and Human Physiology, Faculty of Biology, University of Athens, Athens 15784, Greece.
authors: Kyriaki
authors: K
authors: Ioannou
authors: Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors: Kai Fan
authors: KF
authors: Cheng
authors: Department of Pharmacology, Yale University, New Haven, CT 06510, USA.
authors: Gregg V
authors: GV
authors: Crichlow
authors: Department of Animal and Human Physiology, Faculty of Biology, University of Athens, Athens 15784, Greece.
authors: Anastasios I
authors: AI
authors: Birmpilis
authors: Department of Pharmacology, Yale University, New Haven, CT 06510, USA.
authors: Elias J
authors: EJ
authors: Lolis
authors: Department of Animal and Human Physiology, Faculty of Biology, University of Athens, Athens 15784, Greece.
authors: Ourania E
authors: OE
authors: Tsitsilonis
authors: Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors: Yousef
authors: Y
authors: Al-Abed
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D020134:Catalytic Domain / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D000970:Antineoplastic Agents; C000598426:ISO-66; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D010636:Phenols; D054852:Small Molecule Libraries