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

Dan Niculescu-Duvaz; Ion Niculescu-Duvaz; Bart M.J.M. Suijkerbuijk; Delphine Ménard; Alfonso Zambon; Lawrence Davies; Jean-Francois Pons; Steven Whittaker; Richard Marais; Caroline J. Springer

doi:10.1016/j.bmc.2012.12.035

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

Dan Niculescu-Duvaz, Ion Niculescu-Duvaz, Bart M.J.M. Suijkerbuijk, Delphine Ménard, Alfonso Zambon, Lawrence Davies, Jean-Francois Pons, Steven Whittaker, Richard Marais, Caroline J. Springer

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1284-1304
Number of pages	21
Journal	Bioorganic & Medicinal Chemistry
Volume	21
Issue number	5
DOIs	https://doi.org/10.1016/j.bmc.2012.12.035
Publication status	Published - 1 Mar 2013

Keywords

BRAF
Kinase inhibitors
Anticancer
Melanoma
Triarylimidazole

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2012.12.035

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Niculescu-Duvaz, D., Niculescu-Duvaz, I., Suijkerbuijk, B. M. J. M., Ménard, D., Zambon, A., Davies, L., Pons, J.-F., Whittaker, S., Marais, R., & Springer, C. J. (2013). Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents. Bioorganic & Medicinal Chemistry, 21(5), 1284-1304. https://doi.org/10.1016/j.bmc.2012.12.035

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

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.",

keywords = "BRAF, Kinase inhibitors, Anticancer, Melanoma, Triarylimidazole",

author = "Dan Niculescu-Duvaz and Ion Niculescu-Duvaz and Suijkerbuijk, {Bart M.J.M.} and Delphine M{\'e}nard and Alfonso Zambon and Lawrence Davies and Jean-Francois Pons and Steven Whittaker and Richard Marais and Springer, {Caroline J.}",

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doi = "10.1016/j.bmc.2012.12.035",

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Niculescu-Duvaz, D, Niculescu-Duvaz, I, Suijkerbuijk, BMJM, Ménard, D, Zambon, A, Davies, L, Pons, J-F, Whittaker, S, Marais, R & Springer, CJ 2013, 'Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents.', Bioorganic & Medicinal Chemistry, vol. 21, no. 5, pp. 1284-1304. https://doi.org/10.1016/j.bmc.2012.12.035

TY - JOUR

T1 - Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents.

AU - Niculescu-Duvaz, Dan

AU - Niculescu-Duvaz, Ion

AU - Suijkerbuijk, Bart M.J.M.

AU - Ménard, Delphine

AU - Zambon, Alfonso

AU - Davies, Lawrence

AU - Pons, Jean-Francois

AU - Whittaker, Steven

AU - Marais, Richard

AU - Springer, Caroline J.

PY - 2013/3/1

Y1 - 2013/3/1

N2 - 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.

AB - 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.

KW - BRAF

KW - Kinase inhibitors

KW - Anticancer

KW - Melanoma

KW - Triarylimidazole

UR - http://europepmc.org/abstract/med/23376011

U2 - 10.1016/j.bmc.2012.12.035

DO - 10.1016/j.bmc.2012.12.035

M3 - Article

C2 - 23376011

SN - 0968-0896

VL - 21

SP - 1284

EP - 1304

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 5

ER -

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

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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