RESUMO
The Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is a key target in anticancer drug design. A novel series of pyrimidylpyrrole ERK inhibitors has been identified. Discovery of a conformational change for lead compound 2, when bound to ERK2 relative to antitarget GSK3, enabled structure-guided selectivity optimization, which led to the discovery of 11e, a potent, selective, and orally bioavailable inhibitor of ERK.
Assuntos
Desenho de Fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Conformação Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirróis/química , Pirróis/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/química , Modelos Moleculares , Especificidade por SubstratoRESUMO
The Ras/Raf/MEK/ERK signal transduction is a key oncogenic pathway implicated in a variety of human cancers. We have identified a novel series of pyrazolylpyrroles as inhibitors of ERK. Aided by the discovery of two distinct binding modes for the pyrazolylpyrrole scaffold, structure-guided optimization culminated in the discovery of 6p, a potent and selective inhibitor of ERK.
