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. © 2010 Elsevier Ltd. All rights reserved.
Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds / Niculescu Duvaz, D., Niculescu Duvaz, I., Suijkerbuijk, B.M.J.M., Ménard, D., Zambon, A., Nourry, A., Davies, L., Manne, H.A., Friedlos, F., Ogilvie, L., Hedley, D., Takle, A.K., Wilson, D.M., Pons, J.F., Coulter, T., Kirk, R., Cantarino, N., Whittaker, S., Marais, R., Springer, C.J.. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 18:18(2010), pp. 6934-6952. [10.1016/j.bmc.2010.06.031]
Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds
ZAMBON, Alfonso;
2010
Abstract
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. © 2010 Elsevier Ltd. All rights reserved.
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