Loading...
Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents.
Niculescu-Duvaz, D Niculescu-Duvaz, I Suijkerbuijk, B Ménard, D Zambon, A Davies, L Pons, J Whittaker, S Marais, Richard Springer, C
Niculescu-Duvaz, D
Niculescu-Duvaz, I
Suijkerbuijk, B
Ménard, D
Zambon, A
Davies, L
Pons, J
Whittaker, S
Marais, Richard
Springer, C
Citations
Altmetric:
Abstract
The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC(50)=190 nM and with cellular GI(50)=2100 nM, and 6-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC(50)=9 nM and GI(50)=220 nM.
Description
Date
2013-03-01
Publisher
Collections
Keywords
Type
Article
Citation
Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents. 2013, 21 (5):1284-304 Bioorg Med Chem