Li Qing-Shan, Lü Xian-Hai, Yang Yang, Ruan Ban-Feng, Yao Ri-Sheng, Liao Chen-Zhong
School of Medical Engineering, Hefei University of Technology, Hefei 230009, P. R. China, (phone/fax: +86-551-62904675); Key Laboratory of Green Pesticide and Agriculture Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, P. R. China.
Chem Biodivers. 2015 Jan;12(1):116-32. doi: 10.1002/cbdv.201400143.
Due to the rising incidence and lack of effective treatments, malignant melanoma is the most dangerous form of skin cancer, so that new treatment strategies are urgently needed. Several recent developments indicate that the V600E mutant BRAF (BRAF(V600E) ) is a validated target for antimelanoma-drug development. Based on in silico screening results, a series of novel pyrazole derivatives has been designed, synthesized, and evaluated in vitro for their inhibitory activities against BRAF(V600E) melanoma cells. Compound 3d exhibited the most potent inhibitory activity with an IC50 value of 0.63 μM for BRAF(V600E) and a GI50 value of 0.61 μM for mutant BRAF-dependent cells. Furthermore, the QSAR modeling and the docking simulation of inhibitor analogs provide important pharmacophore clues for further structural optimization.
由于发病率不断上升且缺乏有效的治疗方法，恶性黑色素瘤是最危险的皮肤癌形式，因此迫切需要新的治疗策略。最近的几项进展表明，V600E突变型BRAF（BRAF(V600E)）是抗黑色素瘤药物开发的一个经过验证的靶点。基于计算机筛选结果，设计、合成了一系列新型吡唑衍生物，并在体外评估了它们对BRAF(V600E)黑色素瘤细胞的抑制活性。化合物3d表现出最有效的抑制活性，对BRAF(V600E)的IC50值为0.63 μM，对突变型BRAF依赖性细胞的GI50值为0.61 μM。此外，抑制剂类似物的QSAR建模和对接模拟为进一步的结构优化提供了重要的药效团线索。
Zotero 插件