Subtly Modulating Glycogen Synthase Kinase 3 ß: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases.
J Med Chem
; 60(12): 4983-5001, 2017 06 22.
Article
em En
| MEDLINE
| ID: mdl-28548834
ABSTRACT
Glycogen synthase kinase 3 ß (GSK-3ß) is a central target in several unmet diseases. To increase the specificity of GSK-3ß inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3ß activity. Design synthesis, structure-activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3ß are presented here. Furthermore, we show how allosteric binders may overcome the ß-catenin side effects associated with strong GSK-3ß inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3ß may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3ß inhibition exhibits therapeutic effects.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinase 3 da Glicogênio Sintase
/
Inibidores Enzimáticos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Espanha