title: Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds.
abstract: V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin-4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methyl-piperazin-1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Dan
authors.initials: D
authors.lastname: Niculescu-Duvaz
authors.forename: Ion
authors.initials: I
authors.lastname: Niculescu-Duvaz
authors.forename: Bart M J M
authors.initials: BM
authors.lastname: Suijkerbuijk
authors.forename: Delphine
authors.initials: D
authors.lastname: Ménard
authors.forename: Alfonso
authors.initials: A
authors.lastname: Zambon
authors.forename: Arnaud
authors.initials: A
authors.lastname: Nourry
authors.forename: Lawrence
authors.initials: L
authors.lastname: Davies
authors.forename: Helen A
authors.initials: HA
authors.lastname: Manne
authors.forename: Frank
authors.initials: F
authors.lastname: Friedlos
authors.forename: Lesley
authors.initials: L
authors.lastname: Ogilvie
authors.forename: Douglas
authors.initials: D
authors.lastname: Hedley
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Takle
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pons
authors.forename: Tom
authors.initials: T
authors.lastname: Coulter
authors.forename: Ruth
authors.initials: R
authors.lastname: Kirk
authors.forename: Neus
authors.initials: N
authors.lastname: Cantarino
authors.forename: Steven
authors.initials: S
authors.lastname: Whittaker
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D005260:Female; D005663:Furans / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D005663:Furans; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C029899:imidazole; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C039281:furan