9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: design, synthesis, and biological evaluation.
J Med Chem
; 52(15): 4743-56, 2009 Aug 13.
Article
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| MEDLINE
| ID: mdl-19572547
ABSTRACT
A novel series of potent dual Src/Abl kinase inhibitors based on a 9-(arenethenyl)purine core has been identified. Unlike traditional dual Src/Abl inhibitors targeting the active enzyme conformation, these inhibitors bind to the inactive, DFG-out conformation of both kinases. Extensive SAR studies led to the discovery of potent and orally bioavailable inhibitors, some of which demonstrated in vivo efficacy. Once-daily oral administration of inhibitor 9i (AP24226) significantly prolonged the survival of mice injected intravenously with wild type Bcr-Abl expressing Ba/F3 cells at a dose of 10 mg/kg. In a separate model, oral administration of 9i to mice bearing subcutaneous xenografts of Src Y527F expressing NIH 3T3 cells elicited dose-dependent tumor shrinkage with complete tumor regression observed at the highest dose. Notably, several inhibitors (e.g., 14a, AP24163) exhibited modest cellular potency (IC50 = 300-400 nM) against the Bcr-Abl mutant T315I, a variant resistant to all currently marketed therapies for chronic myeloid leukemia.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Purinas
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Diseño de Fármacos
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Proteínas Proto-Oncogénicas c-abl
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Familia-src Quinasas
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Inhibidores de Proteínas Quinasas
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos