Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
Bioorg Med Chem. 2010 Sep 15;18(18):6934-52. doi: 10.1016/j.bmc.2010.06.031. Epub 2010 Jun 15.
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.
V-RAF 鼠肉瘤病毒致癌基因同源物 B1（BRAF）是一种丝氨酸/苏氨酸特异性蛋白激酶，在皮肤黑色素瘤和许多其他癌症中高频突变。抑制突变型 BRAF 是治疗黑色素瘤的一种有吸引力的治疗方法。一种带有苯并吡唑基团的三芳基咪唑并嘧啶类 BRAF 抑制剂（二甲基-[2-（4-（5-[4-（1H-吡唑-3-基）-苯基]-4-吡啶-4-基-1H-咪唑-2-基）苯氧基）-乙基]-胺，1a）被鉴定为有效的 BRAF 抑制剂。基于这一起点，我们合成了一系列类似物，发现了 6-{2-[4-（4-甲基-哌嗪-1-基）-苯基]-5-吡啶-4-基-3H-咪唑-4-基}-2,4-二氢茚并[1,2-c]吡唑（1j），在三个测定中具有纳摩尔的活性：体外抑制纯化的突变型 BRAF 活性；抑制 BRAF 突变型黑色素瘤细胞系中致癌 BRAF 驱动的细胞外调节激酶（ERK）激活；以及抑制这些细胞的增殖。
