title: Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF): increasing cellular potency through optimization of a distal heteroaromatic group.
abstract: We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A-B-C system (where A is a hinge binding pyrido[4,5-b]imidazolone system, B is an aryl spacer group, and C is a heteroaromatic group) were potent against purified (V600E)BRAF in vitro but were less potent in accompanying cellular assays. Substitution of different aromatic heterocycles for the phenyl based C-ring is evaluated herein as a potential means of improving the cellular potencies of these inhibitors. Substituted pyrazoles, particularly 3-tert-butyl-1-aryl-1H-pyrazoles, increase the cellular potencies without detrimental effects on the potency on isolated (V600E)BRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, (V600E)BRAF, its downstream signaling in cells [as measured by the reduction of the phosphorylation of extracellular regulated kinase (ERK)], and the proliferation of mutant BRAF-dependent cells. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo.
authors.affiliation: The Institute of Cancer Research, Cancer Research UK Centre for Cancer Therapeutics, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Bart M J M
authors.initials: BM
authors.lastname: Suijkerbuijk
authors.forename: Ion
authors.initials: I
authors.lastname: Niculescu-Duvaz
authors.forename: Catherine
authors.initials: C
authors.lastname: Gaulon
authors.forename: Harmen P
authors.initials: HP
authors.lastname: Dijkstra
authors.forename: Dan
authors.initials: D
authors.lastname: Niculescu-Duvaz
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 M
authors.initials: LM
authors.lastname: Ogilvie
authors.forename: Douglas
authors.initials: D
authors.lastname: Hedley
authors.forename: Filipa
authors.initials: F
authors.lastname: Lopes
authors.forename: Natasha P U
authors.initials: NP
authors.lastname: Preece
authors.forename: Javier
authors.initials: J
authors.lastname: Moreno-Farre
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Ruth
authors.initials: R
authors.lastname: Kirk
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; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D027384:Oncogene Proteins v-raf / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009053:Sarcoma Viruses, Murine / Q000201:enzymology*; D017385:Sequence Homology; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D027384:Oncogene Proteins v-raf; D048493:Proto-Oncogene Proteins B-raf