Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2.
Bioorg Med Chem
; 18(2): 707-18, 2010 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-20022510
ABSTRACT
5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were identified from high throughput screening of a kinase-focussed compound library. Rapid exploration of the hits through straightforward chemistry established structure-activity relationships and a proposed ATP-competitive binding mode which was verified by X-ray crystallography of several analogues bound to CHK2. Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and dioxane groups which improved the affinity and the selectivity of the compounds for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be successfully replaced by acyclic omega-aminoalkylamides, which made additional polar interactions within the binding site and led to more potent inhibitors of CHK2. Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
/
Inibidores de Proteínas Quinases
/
Aminopiridinas
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2010
Tipo de documento:
Article