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 IC50 = 190 nM and with cellular GI50 = 2100 nM, and 6-2-[4-(2- dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl-naphthalen-1-ol (1q) with IC50 = 9 nM and GI50 = 220 nM. © 2012 Elsevier Ltd. All rights reserved.

Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents / Niculescu Duvaz, Dan; Niculescu Duvaz, Ion; Suijkerbuijk, Bart M. J. M.; Ménard, Delphine; Zambon, Alfonso; Davies, Lawrence; Pons, Jean Francois; Whittaker, Steven; Marais, Richard; Springer, Caroline J.. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 21:5(2013), pp. 1284-1304. [10.1016/j.bmc.2012.12.035]

Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents

ZAMBON, Alfonso;
2013

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 IC50 = 190 nM and with cellular GI50 = 2100 nM, and 6-2-[4-(2- dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl-naphthalen-1-ol (1q) with IC50 = 9 nM and GI50 = 220 nM. © 2012 Elsevier Ltd. All rights reserved.
21
5
1284
1304
Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents / Niculescu Duvaz, Dan; Niculescu Duvaz, Ion; Suijkerbuijk, Bart M. J. M.; Ménard, Delphine; Zambon, Alfonso; Davies, Lawrence; Pons, Jean Francois; Whittaker, Steven; Marais, Richard; Springer, Caroline J.. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 21:5(2013), pp. 1284-1304. [10.1016/j.bmc.2012.12.035]
Niculescu Duvaz, Dan; Niculescu Duvaz, Ion; Suijkerbuijk, Bart M. J. M.; Ménard, Delphine; Zambon, Alfonso; Davies, Lawrence; Pons, Jean Francois; Whittaker, Steven; Marais, Richard; Springer, Caroline J.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1138871
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