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
| Autor: | Catherine Gaulon, Filipa Lopes, Arnaud Nourry, Steven R. Whittaker, Richard Marais, Frank Friedlos, Alfonso Zambon, Delphine Menard, Bart M. J. M. Suijkerbuijk, Lesley Ogilvie, Helen A. Manne, Ion Niculescu-Duvaz, Lawrence Davies, Harmen P. Dijkstra, Javier Moreno-Farre, Dan Niculescu-Duvaz, Natasha Preece, Douglas Hedley, Caroline J. Springer, Ruth Kirk, Florence I. Raynaud |
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| Rok vydání: | 2010 |
| Předmět: |
MAPK/ERK pathway
Models Molecular Proto-Oncogene Proteins B-raf Animals Cell Line Tumor Female Humans Inhibitory Concentration 50 Mice Molecular Conformation Oncogene Proteins v-raf Protein Kinase Inhibitors Sarcoma Viruses Murine Structure-Activity Relationship Drug Design Sequence Homology Molecular Medicine Drug Discovery3003 Pharmaceutical Science Cell Line Models In vivo Drug Discovery Structure–activity relationship Murine Tumor Kinase Chemistry Molecular Sarcoma Viruses Molecular biology Signal transduction V600E |
| Zdroj: | Journal of medicinal chemistry. 53(7) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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