CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
Cancer Cell
; 19(5): 679-90, 2011 May 17.
Article
em En
| MEDLINE
| ID: mdl-21575866
ABSTRACT
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.
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Base de dados:
MEDLINE
Assunto principal:
Piperidinas
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Carbazóis
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Receptores Proteína Tirosina Quinases
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Resistencia a Medicamentos Antineoplásicos
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Inibidores de Proteínas Quinases
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Neoplasias
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Antineoplásicos
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article