Aurora isoform selectivity: design and synthesis of imidazo[4,5-b]pyridine derivatives as highly selective inhibitors of Aurora-A kinase in cells.
J Med Chem
; 56(22): 9122-35, 2013 Nov 27.
Article
en En
| MEDLINE
| ID: mdl-24195668
ABSTRACT
Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket (L215, T217, and R220). Exploiting these differences, crystal structures of ligand-Aurora protein interactions formed the basis of a design principle for imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine derivatization led to the discovery of highly selective inhibitors, such as compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells, 28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E mutant was significantly less sensitive to inhibition by 28c and 40f compared to the Aurora-A wild type, suggesting that the T217 residue plays a critical role in governing the observed isoform selectivity for Aurora-A inhibition. These compounds are useful small-molecule chemical tools to further explore the function of Aurora-A in cells.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
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Inhibidores de Proteínas Quinasas
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Aurora Quinasa A
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Aurora Quinasa B
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Imidazoles
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2013
Tipo del documento:
Article
País de afiliación:
Reino Unido