RESUMEN
Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.
Asunto(s)
Amidas/farmacología , Ciclopropanos/farmacología , Citocinas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Adenosina/análogos & derivados , Amidas/síntesis química , Amidas/química , Cristalografía por Rayos X , Ciclopropanos/síntesis química , Ciclopropanos/química , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Nicotinamida Fosforribosiltransferasa/metabolismo , Fenotipo , Relación Estructura-ActividadRESUMEN
[This corrects the article DOI: 10.1021/acsomega.8b00202.].
RESUMEN
Methuosis is a form of nonapoptotic cell death characterized by the accumulation of macropinosome-derived vacuoles. Herein, we identify PIKFYVE, a class III phosphoinositide (PI) kinase, as the protein target responsible for the methuosis-inducing activity of indolyl-pyridinyl-propenones (3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one). We further characterize the effects of chemical substitutions at the 2- and 5-indolyl positions on cytoplasmic vacuolization and PIKFYVE binding and inhibitory activity. Our study provides a better understanding of the mechanism of methuosis-inducing indolyl-pyridinyl-propenones.