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Discovery of novel inhibitors of the tautomerase activity of macrophage Migration Inhibitory Factor (MIF)



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Cleofé Zapatero, María and Pérez, Paloma and Vázquez, María Jesús and Colmenarejo Sánchez, Gonzalo and Frailes, Maite de los and Ramón Olayo, Fernando Antonio (2015) Discovery of novel inhibitors of the tautomerase activity of macrophage Migration Inhibitory Factor (MIF). Journal of Biomolecular Screening, 21 (5). pp. 446-458. ISSN 1087-0571

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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine associated with multiple diseases, including neurodegenerative disorders. With the ultimate goal of providing novel chemotypes as starting points for development of disease-modifying therapeutics for neurodegeneration, we endeavored to screen the GSK compound collection for MIF inhibitors using a miniaturized, activity-based kinetic assay. The assay monitors the increase in absorbance at 320 nm resulting from keto-to-enol tautomerization of 4-hydroxyphenylpyruvate, a reaction catalyzed by MIF. We ran a fulldiversity screen evaluating the inhibitory activity of 1.6 million compounds. Primary hits were confirmed and retested in an orthogonal assay measuring tautomerization of l-dopachrome methyl ester by the decrease in absorbance at 475 nm in kinetic mode. Selected compounds were progressed to medium-throughput mode-of-inhibition studies, which included time dependence, enzyme concentration dependence, and reversibility of their inhibitory effect. With these results and after inspection of the physicochemical properties of compounds, 17 chemotypes were prioritized and progressed to further stages of validation and characterization to better assess their therapeutic potential.

Item Type:Article
Uncontrolled Keywords:macrophage migration inhibitory factor, MIF, high-throughput screening, tautomerase, 4-hydroxyphenylpyruvic acid, l-dopachrome methyl ester
Subjects:Medical sciences > Biology
Medical sciences > Biology > Molecular biology
ID Code:43414
Deposited On:16 Jun 2017 17:05
Last Modified:16 Jun 2017 17:05

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