A Novel, Macrophage Migration Inhibitory Factor Suicide Substrate Inhibits Motility and Growth of Lung Cancer Cells
| Autor: | Randall Riggs, John O. Trent, Richard Bucala, Swen Zierow, Lin Leng, Millicent Winner, Jason B. Meier, Elias Lolis, Robert A. Mitchell, Beatriz E. Rendon, Gregg V. Crichlow, Ned B. Smith |
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| Rok vydání: | 2008 |
| Předmět: |
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Molecular Cancer Research medicine.medical_specialty Chemokine Lung Neoplasms medicine.medical_treatment Cell Growth Processes Adenocarcinoma Biology Article Growth factor receptor Cell Movement Cell Line Tumor Internal medicine otorhinolaryngologic diseases medicine Humans Autocrine signalling Macrophage Migration-Inhibitory Factors Growth factor Isoxazoles Small molecule Cell biology Intramolecular Oxidoreductases Pyrimidines Cytokine Endocrinology Oncology Cell culture biology.protein Macrophage migration inhibitory factor |
| Zdroj: | Cancer Research. 68:7253-7257 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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 ∼5× to 10× 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 10× to 20× lower than that of parental 4-IPP. [Cancer Res 2008;68(18):7253–7] |
| Databáze: | OpenAIRE |
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