期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 18, 页码 6934-6952出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.06.031
关键词
BRAF; Kinase inhibitors; Anticancer; Melanoma; Triarylimidazole; Dihydroindenopyrazole
资金
- Wellcome Trust [080333/Z/06/Z]
- Cancer Research UK [C309/A8274, C107/A10433]
- Isle of Man Anti-Cancer Association
- Institute of Cancer Research
- NHS
- Wellcome Trust [080333/Z/06/Z] Funding Source: Wellcome Trust
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-methylpiperazin- 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. (C) 2010 Elsevier Ltd. All rights reserved.
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