Discovery of mitogen-activated protein kinase-interacting kinase 1 inhibitors by a comprehensive fragment-oriented virtual screening approach.
J Med Chem
; 53(18): 6618-28, 2010 Sep 23.
Article
en En
| MEDLINE
| ID: mdl-20722422
ABSTRACT
Mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate the oncogene eIF4E on serine 209. This phosphorylation has been reported to be required for its oncogenic activity. To investigate if pharmacological inhibition of MNK1 could be useful for the treatment of cancers, we pursued a comprehensive virtual screening approach to rapidly identify pharmacological tools for target validation and to find optimal starting points for a plausible medicinal chemistry project. A collection of 1236 compounds, selected from a library of 42 168 compounds and a database of 18.8 million structures, were assayed. Of the identified hits, 26 were found to have IC(50) values less than 10 µM (2.10% hit rate). The most potent compound had an IC(50) value of 117 nM, and 73.1% of these hits were fragments. The hits were characterized by a high ligand efficiency (0.32-0.52 kcal/mol per heavy atom). Ten different chemical scaffolds were represented, giving a chemotype/hit ratio of 0.38.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Serina-Treonina Quinasas
/
Péptidos y Proteínas de Señalización Intracelular
/
Antineoplásicos
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2010
Tipo del documento:
Article
País de afiliación:
España