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Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site.
Chem Biol ; 18(2): 177-86, 2011 Feb 25.
Article en En | MEDLINE | ID: mdl-21338916
ABSTRACT
c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Pirazoles / Proteínas Proto-Oncogénicas c-abl / Descubrimiento de Drogas / Hidantoínas Límite: Humans Idioma: En Revista: Chem Biol Asunto de la revista: BIOLOGIA / BIOQUIMICA / QUIMICA Año: 2011 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Pirazoles / Proteínas Proto-Oncogénicas c-abl / Descubrimiento de Drogas / Hidantoínas Límite: Humans Idioma: En Revista: Chem Biol Asunto de la revista: BIOLOGIA / BIOQUIMICA / QUIMICA Año: 2011 Tipo del documento: Article País de afiliación: Estados Unidos