Identification of small-molecule inhibitors of the JIP-JNK interaction.
Biochem J
; 420(2): 283-94, 2009 May 13.
Article
em En
| MEDLINE
| ID: mdl-19243309
ABSTRACT
JNK1 (c-Jun N-terminal kinase 1) plays a crucial role in the regulation of obesity-induced insulin resistance and is implicated in the pathology of Type 2 diabetes. Its partner, JIP1 (JNK-interacting protein 1), serves a scaffolding function that facilitates JNK1 activation by MKK4 [MAPK (mitogen-activated protein kinase) kinase 4] and MKK7 (MAPK kinase 7). For example, reduced insulin resistance and JNK activation are observed in JIP1-deficient mice. On the basis of the in vivo efficacy of a cell-permeable JIP peptide, the JIP-JNK interaction appears to be a potential target for JNK inhibition. The goal of the present study was to identify small-molecule inhibitors that disrupt the JIP-JNK interaction to provide an alternative approach for JNK inhibition to ATP-competitive inhibitors. High-throughput screening was performed by utilizing a fluorescence polarization assay that measured the binding of JNK1 to the JIP peptide. Multiple chemical series were identified, revealing two categories of JIP/JNK inhibitors 'dual inhibitors' that are ATP competitive and probably inhibit JIP-JNK binding allosterically, and 'JIP-site binders' that block binding through interaction with the JIP site. A series of polychloropyrimidines from the second category was characterized by biochemical methods and explored through medicinal-chemistry efforts. As predicted, these inhibitors also inhibited full-length JIP-JNK binding and were selective against a panel of 34 representative kinases, including ones in the MAPK family. Overall, this work demonstrates that small molecules can inhibit protein-protein interactions in vitro in the MAPK family effectively and provides strategies for similar approaches within other target families.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos Orgânicos
/
Proteínas Quinases JNK Ativadas por Mitógeno
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Proteínas Adaptadoras de Transdução de Sinal
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article