State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, P. R. China.
Org Biomol Chem. 2013 Oct 7;11(37):6328-37. doi: 10.1039/c3ob40776d.
The RAF-MEK-ERK cascade appears to be intimately involved in the regulation of cell cycle progression and apoptosis. The BRAF(V600E) mutant results in constitutive activation of the ERK pathway, which can lead to cellular growth dysregulation. A series of 5-phenyl-1H-pyrazol derivatives (3a-5e) have been designed and synthesized, and their biological activities were evaluated as potential BRAF(V600E) inhibitors. All the compounds were reported for the first time except 3e, and compound 1-(4-bromo-2-hydroxybenzyl)-3-phenyl-1-(5-phenyl-1H-pyrazol-3-yl)urea (5c) displayed the most potent inhibitory activity (BRAF(V600E) IC50 = 0.19 μM). Antiproliferative assay results indicated that compound 5c possessed high antiproliferative activity against cell lines WM266.4 and A375 in vitro, with IC50 values of 1.50 and 1.32 μM, respectively, which were comparable with the positive control vemurafenib. Docking simulations showed that compound 5c binds tightly to the BRAF(V600E) active site and acts as BRAF(V600E) inhibitor. A 3D-QSAR model was also built to provide more pharmacophore understanding towards designing new agents with more potent BRAF(V600E) inhibitory activity.
RAF-MEK-ERK 级联似乎密切参与细胞周期进程和细胞凋亡的调控。BRAF(V600E)突变导致 ERK 通路的组成性激活，从而导致细胞生长失调。设计并合成了一系列 5-苯基-1H-吡唑衍生物（3a-5e），并评估了它们作为潜在 BRAF(V600E)抑制剂的生物活性。除了 3e 之外，所有化合物均为首次报道，其中 1-(4-溴-2-羟基苄基)-3-苯基-1-(5-苯基-1H-吡唑-3-基)脲（5c）显示出最强的抑制活性（BRAF(V600E)IC50=0.19 μM）。增殖抑制试验结果表明，化合物 5c 对 WM266.4 和 A375 细胞系具有高体外增殖抑制活性，IC50 值分别为 1.50 和 1.32 μM，与阳性对照药 vemurafenib 相当。对接模拟表明，化合物 5c 与 BRAF(V600E)活性位点紧密结合，是一种 BRAF(V600E)抑制剂。还构建了一个 3D-QSAR 模型，为设计具有更强 BRAF(V600E)抑制活性的新型药物提供了更多的药效基团理解。
