Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents.
Authors
Niculescu-Duvaz, DNiculescu-Duvaz, I
Suijkerbuijk, B
Ménard, D
Zambon, A
Davies, L
Pons, J
Whittaker, S
Marais, Richard
Springer, C
Affiliation
The Institute of Cancer Research, Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.Issue Date
2013-03-01
Metadata
Show full item recordAbstract
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.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 ChemJournal
Bioorganic & Medicinal ChemistryDOI
10.1016/j.bmc.2012.12.035PubMed ID
23376011Type
ArticleLanguage
enISSN
1464-3391ae974a485f413a2113503eed53cd6c53
10.1016/j.bmc.2012.12.035
Scopus Count
Collections
Related articles
- Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds.
- Authors: Niculescu-Duvaz D, Niculescu-Duvaz I, Suijkerbuijk BM, Ménard D, Zambon A, Nourry A, Davies L, Manne HA, Friedlos F, Ogilvie L, Hedley D, Takle AK, Wilson DM, Pons JF, Coulter T, Kirk R, Cantarino N, Whittaker S, Marais R, Springer CJ
- Issue date: 2010 Sep 15
- Design, synthesis, and biological evaluation of novel imidazole derivatives possessing terminal sulphonamides as potential BRAF(V600E)inhibitors.
- Authors: Ali EMH, Abdel-Maksoud MS, Ammar UM, Mersal KI, Ho Yoo K, Jooryeong P, Oh CH
- Issue date: 2021 Jan
- Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAF(V600E)/p38α inhibitors.
- Authors: Ali EMH, El-Telbany RFA, Abdel-Maksoud MS, Ammar UM, Mersal KI, Zaraei SO, El-Gamal MI, Choi SI, Lee KT, Kim HK, Lee KH, Oh CH
- Issue date: 2021 Apr 5
- BRAF inhibitors based on an imidazo[4,5]pyridin-2-one scaffold and a meta substituted middle ring.
- Authors: Nourry A, Zambon A, Davies L, Niculescu-Duvaz I, Dijkstra HP, Ménard D, Gaulon C, Niculescu-Duvaz D, Suijkerbuijk BM, Friedlos F, Manne HA, Kirk R, Whittaker S, Marais R, Springer CJ
- Issue date: 2010 Mar 11
- ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells.
- Authors: Cesi G, Walbrecq G, Zimmer A, Kreis S, Haan C
- Issue date: 2017 Jun 8