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Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds

Authors
Journal
Bioorganic & Medicinal Chemistry
0968-0896
Publisher
Elsevier
Publication Date
Volume
18
Issue
18
Identifiers
DOI: 10.1016/j.bmc.2010.06.031
Keywords
  • Braf
  • Kinase Inhibitors
  • Anticancer
  • Melanoma
  • Triarylimidazole
  • Dihydroindenopyrazole
Disciplines
  • Biology
  • Medicine

Abstract

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.

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