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 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.
authors: The Institute of Cancer Research, Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
authors: Dan
authors: D
authors: Niculescu-Duvaz
authors: Ion
authors: I
authors: Niculescu-Duvaz
authors: Bart M J M
authors: BM
authors: Suijkerbuijk
authors: Delphine
authors: D
authors: Ménard
authors: Alfonso
authors: A
authors: Zambon
authors: Lawrence
authors: L
authors: Davies
authors: Jean-Francois
authors: JF
authors: Pons
authors: Steven
authors: S
authors: Whittaker
authors: Richard
authors: R
authors: Marais
authors: Caroline J
authors: CJ
authors: Springer
mesh_terms: D001572:Benzofurans / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D009284:Naphthols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C583000:1-(6-(2-(4-(2-dimethylaminoethoxy)phenyl)-5-(pyridin-4-yl)-1H-imidazol-4-yl)benzo(b)thiophen-3-yl)-2,2,2-trifluoroethanol; C583001:6-(2-(4-(2-dimethylaminoethoxy)phenyl)-5-pyridin-4-yl-3H-imidazol-4-yl)naphthalen-1-ol; D001572:Benzofurans; D007093:Imidazoles; D009284:Naphthols; D047428:Protein Kinase Inhibitors; D013876:Thiophenes; C088015:benzothiophene; C029899:imidazole; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C105430:benzofuran