Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases.
J Biol Chem
; 284(41): 28392-28400, 2009 Oct 09.
Article
em En
| MEDLINE
| ID: mdl-19690175
ABSTRACT
Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. A cell-based imaging assay that monitored the translocation of the Akt effector protein, Forkhead box O (FOXO), from the cytoplasm to the nucleus was employed to screen a collection of 33,992 small molecules. The positive compounds were used to screen kinases known to be involved in FOXO translocation. Pyrazolopyrimidine derivatives were found to be potent FOXO relocators as well as biochemical inhibitors of PI3Kalpha. A combination of virtual screening and molecular modeling led to the development of a structure-activity relationship, which indicated the preferred substituents on the pyrazolopyrimidine scaffold. This leads to the synthesis of ETP-45658, which is a potent and selective inhibitor of phosphoinositide 3-kinases and demonstrates mechanism of action in tumor cell lines and in vivo in treated mice.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
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Pirimidinas
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Núcleo Celular
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Fosfatidilinositol 3-Quinases
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Inibidores Enzimáticos
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Fatores de Transcrição Forkhead
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Inibidores de Fosfoinositídeo-3 Quinase
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article