RESUMEN
Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.
Asunto(s)
Antineoplásicos/farmacología , Compuestos de Bifenilo/farmacología , Ácidos Carboxílicos/farmacología , Inhibidores Enzimáticos/farmacología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Animales , Antineoplásicos/química , Compuestos de Bifenilo/química , Ácidos Carboxílicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dihidroorotato Deshidrogenasa , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Humanos , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Relación Estructura-ActividadRESUMEN
Curcumin is among the more successful chemopreventive compounds investigated in recent years, and is currently in human trials to prevent cancer. The mechanism of action of curcumin is complex and likely multifactorial. We have made the unexpected observation that curcumin strikingly modulates proteins of iron metabolism in cells and in tissues, suggesting that curcumin has properties of an iron chelator. Curcumin increased mRNA levels of ferritin and GSTalpha in cultured liver cells. Unexpectedly, however, although levels of GSTalpha protein increased in parallel with mRNA levels in response to curcumin, levels of ferritin protein declined. Since iron chelators repress ferritin translation, we considered that curcumin may act as an iron chelator. To test this hypothesis, we measured the effect of curcumin on transferrin receptor 1, a protein stabilized under conditions of iron limitation, as well as the ability of curcumin to activate iron regulatory proteins (IRPs). Both transferrin receptor 1 and activated IRP, indicators of iron depletion, increased in response to curcumin. Consistent with the hypothesis that curcumin acts as an iron chelator, mice that were fed diets supplemented with curcumin exhibited a decline in levels of ferritin protein in the liver. These results suggest that iron chelation may be an additional mode of action of curcumin.