Structure-based optimization of tyrosine kinase inhibitor CLM3. Design, synthesis, functional evaluation, and molecular modeling studies.
J Med Chem
; 57(4): 1225-35, 2014 Feb 27.
Article
em En
| MEDLINE
| ID: mdl-24447248
ABSTRACT
Recent advances in the knowledge of thyroid carcinomas development identified receptor tyrosine kinases, like VEGFR2 and RET, as viable and promising targets. Accordingly, their inhibition is emerging as the major therapeutic strategy to treat these pathologies. In this study we describe the synthesis and the functional evaluation of three different series of 4-substituted pyrazolo[3,4-d]pyrimidine derivatives, 8a-g, 9a-g, and 10a-g, designed exploiting a structure-based optimization of the previously developed inhibitor CLM3. Compared to the lead, the novel compounds markedly improved both their inhibitory profile against the target proteins, VEGFR2 and RET, and their antiproliferative efficacy against the medullary thyroid cancer cell line TT. Significantly, compounds 8b, 9c, and 10c proved to block the kinase activity of the mutant RET(V804L), which still lacks effective inhibitors.
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Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article