RESUMO
Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.
Assuntos
Glucosilceramidase/antagonistas & inibidores , Chaperonas Moleculares/química , Chaperonas Moleculares/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Linhagem Celular , Fibroblastos , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/enzimologia , Glucosilceramidase/química , Glucosilceramidase/metabolismo , Humanos , Himecromona/análogos & derivados , Himecromona/análise , Imuno-Histoquímica , Lisossomos/efeitos dos fármacos , Lisossomos/enzimologia , Lisossomos/metabolismo , Espectroscopia de Ressonância Magnética , Microscopia Confocal , Chaperonas Moleculares/síntese química , Quinazolinas/síntese química , Espectrometria de Massas por Ionização por Electrospray , Baço/enzimologia , Baço/metabolismo , Relação Estrutura-AtividadeRESUMO
Pompe disease is a lysosomal storage disease (LSD) caused by a deficiency in the lysosomal enzyme acid alpha-glucosidase. In several LSDs, enzyme inhibitors have been used as small molecule chaperones to facilitate and increase the translocation of mutant protein from the endoplasmic reticulum to the lysosome. Enzyme activators with chaperone activity would be even more desirable as they would not inhibit the enzyme after translocation and might potentiate the activity of the enzyme that is successfully translocated. Herein we report our initial findings of a new series of acid alpha-glucosidase activators.
