Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.
Proc Natl Acad Sci U S A
; 104(1): 270-5, 2007 Jan 02.
Article
em En
| MEDLINE
| ID: mdl-17185414
ABSTRACT
Constitutive overexpression and activation of NPM-ALK fusion protein [t(25)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC(50) values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Proteínas Tirosina Quinases
/
Linfoma Difuso de Grandes Células B
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Inibidores de Proteínas Quinases
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article