A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl.
J Med Chem
; 53(15): 5439-48, 2010 Aug 12.
Article
em En
| MEDLINE
| ID: mdl-20604564
ABSTRACT
The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M351T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Pirimidinonas
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Proteínas Tirosina Quinases
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Proteínas de Fusão bcr-abl
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Compostos Bicíclicos Heterocíclicos com Pontes
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Antineoplásicos
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article