Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors.
Bioorg Med Chem Lett
; 24(11): 2448-52, 2014 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-24767842
ABSTRACT
There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
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Inibidores de Proteínas Quinases
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Descoberta de Drogas
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Indazóis
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article