Structure-based discovery of cellular-active allosteric inhibitors of FAK.
Bioorg Med Chem Lett
; 23(6): 1779-85, 2013 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-23414845
ABSTRACT
In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50=0.64µM) and in cellular assays (IC50=7.1µM). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tiazinas
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Óxidos S-Cíclicos
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Inibidores de Proteínas Quinases
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Proteína-Tirosina Quinases de Adesão Focal
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Compostos Heterocíclicos com 3 Anéis
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Antineoplásicos
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article