Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants.
Blood
; 115(21): 4206-16, 2010 May 27.
Article
em En
| MEDLINE
| ID: mdl-20299508
ABSTRACT
Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I- BCR-ABL (clinically observed in chronic myeloid leukemia), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors), and T674I/M-PDGFRalpha (clinically observed in hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported kinase inhibitors in having the ability to accommodate either a gatekeeper threonine, present in the wild-type forms of these kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor. The distinctive ability of HG-7-85-01 to simultaneously inhibit both wild-type and mutant forms of several kinases of clinical relevance is an important step in the development of the next generation of tyrosine kinase inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Tiazóis
/
Proteínas de Fusão bcr-abl
/
Quinases da Família src
/
Proteínas Proto-Oncogênicas c-kit
/
Receptor alfa de Fator de Crescimento Derivado de Plaquetas
/
Inibidores de Proteínas Quinases
/
Proteínas Mutantes
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Blood
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Marrocos