405554-85-0Relevant academic research and scientific papers
Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds
Niculescu-Duvaz, Dan,Niculescu-Duvaz, Ion,Suijkerbuijk, Bart M.J.M.,Ménard, Delphine,Zambon, Alfonso,Nourry, Arnaud,Davies, Lawrence,Manne, Helen A.,Friedlos, Frank,Ogilvie, Lesley,Hedley, Douglas,Takle, Andrew K.,Wilson, David M.,Pons, Jean-Francois,Coulter, Tom,Kirk, Ruth,Cantarino, Neus,Whittaker, Steven,Marais, Richard,Springer, Caroline J.
experimental part, p. 6934 - 6952 (2010/11/03)
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.
