Discovery of novel inhibitors of Aurora kinases with indazole scaffold: In silico fragment-based and knowledge-based drug design.
Eur J Med Chem
; 124: 186-199, 2016 Nov 29.
Article
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| MEDLINE
| ID: mdl-27573544
ABSTRACT
Aurora kinases have emerged as important anticancer targets so that there are several inhibitors have advanced into clinical study. Herein, we identified novel indazole derivatives as potent Aurora kinases inhibitors by utilizing in silico fragment-based approach and knowledge-based drug design. After intensive hit-to-lead optimization, compounds 17 (dual Aurora A and B), 21 (Aurora B selective) and 30 (Aurora A selective) possessed indazole privileged scaffold with different substituents, which provide sub-type kinase selectivity. Computational modeling helps in understanding that the isoform selectivity could be targeted specific residue in the Aurora kinase binding pocket in particular targeting residues Arg220, Thr217 or Glu177.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Simulación por Computador
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Diseño de Fármacos
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Inhibidores de Proteínas Quinasas
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Aurora Quinasa A
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Indazoles
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2016
Tipo del documento:
Article