A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.
Nat Chem Biol
; 10(10): 853-60, 2014 Oct.
Article
em En
| MEDLINE
| ID: mdl-25195011
ABSTRACT
Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Proteína Quinase 1 Ativada por Mitógeno
/
Sistema de Sinalização das MAP Quinases
/
Proteína Quinase 3 Ativada por Mitógeno
/
Inibidores Enzimáticos
/
Indazóis
/
Antineoplásicos
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Revista:
Nat Chem Biol
Assunto da revista:
BIOLOGIA
/
QUIMICA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Reino Unido