title: A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells.
abstract: Although chemokine and growth factor receptors are attractive and popular targets for cancer therapeutic intervention, structure-based targeting of the ligands themselves is generally not considered practical. New evidence indicates that a notable exception to this is macrophage migration inhibitory factor (MIF). MIF, an autocrine- and paracrine-acting cytokine/growth factor, plays a pivotal role in both the initiation and maintenance of neoplastic diseases. MIF possesses a nonphysiologic enzymatic activity that is evolutionarily well-conserved. Although small molecule antagonists of MIFs enzymatic active site have been reported to inhibit biological activities of MIF, universally high IC(50)s have limited their clinical appeal. Using a computational virtual screening strategy, we have identified a unique small molecule inhibitor that serves as a suicide substrate for MIF, resulting in the covalent modification of the catalytically active NH(2)-terminal proline. Our studies further reveal that this compound, 4-iodo-6-phenylpyrimidine (4-IPP), is approximately 5x to 10x times more potent in blocking MIF-dependent catalysis and lung adenocarcinoma cell migration and anchorage-independent growth than the prototypical MIF inhibitor, ISO-1. Finally, using an in silico combinatorial optimization strategy, we have identified four unique congeners of 4-IPP that exhibit MIF inhibitory activity at concentrations 10x to 20x lower than that of parental 4-IPP.
authors.affiliation: Molecular Targets Program, University of Louisville, KY, USA.
authors.forename: Millicent
authors.initials: M
authors.lastname: Winner
authors.forename: Jason
authors.initials: J
authors.lastname: Meier
authors.forename: Swen
authors.initials: S
authors.lastname: Zierow
authors.forename: Beatriz E
authors.initials: BE
authors.lastname: Rendon
authors.forename: Gregg V
authors.initials: GV
authors.lastname: Crichlow
authors.forename: Randall
authors.initials: R
authors.lastname: Riggs
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Ned
authors.initials: N
authors.lastname: Smith
authors.forename: Elias
authors.initials: E
authors.lastname: Lolis
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mitchell
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; C532251:4-iodo-6-phenylpyrimidine; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D011743:Pyrimidines; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
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