RT Journal Article
T1 Discovery of novel inhibitors of the tautomerase activity of macrophage Migration Inhibitory Factor (MIF)
A1 Cleofé Zapatero, María
A1 Pérez, Paloma
A1 Vázquez, María Jesús
A1 Colmenarejo Sánchez, Gonzalo
A1 Frailes, Maite de los
A1 Ramón Olayo, Fernando Antonio
AB 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.
PB SAGE Publishing
SN 1087-0571
YR 2015
FD 2015
LK https://hdl.handle.net/20.500.14352/35499
UL https://hdl.handle.net/20.500.14352/35499
LA eng
DS Docta Complutense
RD 10 abr 2025