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 V600EBRAF 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 V600EBRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, V600EBRAF, 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. © 2010 American Chemical Society.
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|Data di pubblicazione:||2010|
|Titolo:||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|
|Autori:||Suijkerbuijk, Bart M.J.M.; Niculescu-Duvaz, Ion; Gaulon, Catherine; Dijkstra, Harmen P.; Niculescu-Duvaz, Dan; Ménard, Delphine; Zambon, Alfonso; Nourry, Arnaud; Davies, Lawrence; Manne, Helen A.; Friedlos, Frank; Ogilvie, Lesley M.; Hedley, Douglas; Lopes, Filipa; Preece, Natasha P.U.; Moreno-Farre, Javier; Raynaud, Florence I.; Kirk, Ruth; Whittaker, Steven; Marais, Richard; Springer, Caroline J|
|Digital Object Identifier (DOI):||10.1021/jm900607f|
|Appare nelle tipologie:||Articolo su rivista|
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