1217299-13-2Relevant academic research and scientific papers
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
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.
supporting information; experimental part, p. 2741 - 2756 (2010/09/04)
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.
