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3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.
Bioorg Med Chem Lett ; 16(23): 6049-53, 2006 Dec 01.
Article en En | MEDLINE | ID: mdl-16978863
The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC(50)=0.30nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.
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Base de datos: MEDLINE Asunto principal: Proteínas Quinasas / Inhibidores de Proteínas Quinasas / Indazoles Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2006 Tipo del documento: Article
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Base de datos: MEDLINE Asunto principal: Proteínas Quinasas / Inhibidores de Proteínas Quinasas / Indazoles Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2006 Tipo del documento: Article