Targeting the Shc-EGFR interaction with indomethacin inhibits MAP kinase pathway signalling.
Cancer Lett
; 457: 86-97, 2019 08 10.
Article
en En
| MEDLINE
| ID: mdl-31100409
ABSTRACT
Receptor tyrosine kinase (RTK)-mediated hyperactivation of the MAPK/Erk pathway is responsible for a large number of pathogenic outcomes including many cancers. Considerable effort has been directed at targeting this pathway with varying degrees of long term therapeutic success. Under non-stimulated conditions Erk is bound to the adaptor protein Shc preventing aberrant signalling by sequestering Erk from activation by Mek. Activated RTK recruits Shc, via its phosphotyrosine binding (PTB) domain (ShcPTB), precipitating the release of Erk to engage in a signalling response. Here we describe a novel approach to inhibition of MAP kinase signal transduction through attempting to preserve the Shc-Erk complex under conditions of activated receptor. A library of existing drug molecules was computationally screened for hits that would bind to the ShcPTB and block its interaction with the RTKs EGFR and ErbB2. The primary hit from the screen was indomethacin, a non-steroidal anti-inflammatory drug. Validation of this molecule in vitro and in cellular efficacy studies in cancer cells provides proof of principle of the approach to pathway down-regulation and a potential optimizable lead compound.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Antiinflamatorios no Esteroideos
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Indometacina
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Sistema de Señalización de MAP Quinasas
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Proteínas Adaptadoras de la Señalización Shc
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Reposicionamiento de Medicamentos
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Neoplasias
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Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Cancer Lett
Año:
2019
Tipo del documento:
Article
País de afiliación:
Reino Unido