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A Novel, Macrophage Migration Inhibitory Factor Suicide Substrate Inhibits Motility and Growth of Lung Cancer Cells

¹ Molecular Targets Program, ² Structural Biology Program, JG Brown Cancer Center, ³ Department of Pharmacology and Toxicology, University of Louisville, and ⁴ Advanced Cancer Therapeutics, Louisville, Kentucky; and Departments of ⁵ Pharmacology and ⁶ Internal Medicine, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Robert A. Mitchell, University of Louisville, Delia Baxter Research Building, Suite 204B, 580 South Preston Street, Louisville, KY. Phone: 502-852-7698; Fax: 502-852-5679; E-mail: robert.mitchell{at}louisville.edu.

Key Words: anchorage independence • cancer • enzyme • inhibitor • migration • tautomerase

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 IC₅₀s 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 NH₂-terminal proline. Our studies further reveal that this compound, 4-iodo-6-phenylpyrimidine (4-IPP), is 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. [Cancer Res 2008;68(18):7253–7]