A small molecule-kinase interaction map for clinical kinase inhibitors.
Nat Biotechnol
; 23(3): 329-36, 2005 Mar.
Article
em En
| MEDLINE
| ID: mdl-15711537
ABSTRACT
Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Pirimidinas
/
Preparações Farmacêuticas
/
Desenho de Fármacos
/
Proteínas de Escherichia coli
/
Mapeamento de Interação de Proteínas
/
Inibidores de Proteínas Quinases
/
Escherichia coli
Tipo de estudo:
Evaluation_studies
/
Prognostic_studies
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article