N-(3-Ethynyl-2,4-difluorophenyl)sulfonamide Derivatives as Selective Raf Inhibitors
N-(3-Ethynyl-2,4-difluorophenyl)sulfonamide Derivatives as Selective Raf Inhibitors
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作为选择性 Raf 抑制剂的 N-(3-乙炔基-2,4-二氟苯基)磺酰胺衍生物
DOI：
10.1021/acsmedchemlett.5b00039
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发表时间：
2015-05-01
影响因子：
4.2
通讯作者：
Ding, Ke
中科院分区：
文献类型：
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作者：
Li, Yingjun;Cheng, Huimin;Ding, Ke
一系列N-（3-乙基-2,4-二氟苯基）磺酰胺被鉴定为新的选择性Raf抑制剂。这些化合物对B-Raf（V600E）具有低纳摩尔IC50值的抑制作用，并在对468种激酶的选择性分析中表现出良好的靶标特异性。它们强烈抑制一组具有B-Raf（V600E）突变的人类癌细胞系和患者来源的黑色素瘤细胞的增殖，而对具有B-Raf（WT）的细胞的效力显着降低。这些化合物还显示出良好的药代动力学特性，在B-Raf（V600E）突变的col205人结直肠癌细胞的异种移植小鼠模型中显示出显著的体内抗肿瘤功效，支持其作为进一步抗癌药物发现的有希望的先导化合物。
A series of N-(3-ethynyl-2,4-difluorophenyl)sulfonamides were identified as new selective Raf inhibitors. The compounds potently inhibit B-Raf(V600E) with low nanomolar IC50 values and exhibit excellent target specificity in a selectivity profiling investigation against 468 kinases. They strongly suppress proliferation of a panel of human cancer cell lines and patient-derived melanoma cells with B-Raf(V600E) mutation while being significantly less potent to the cells with B-Raf(WT). The compounds also display favorable pharmacokinetic properties with a preferred example (3s) demonstrating significant in vivo antitumor efficacy in a xenograft mouse model of B-Raf(V600E) mutated Colo205 human colorectal cancer cells, supporting it as a promising lead compound for further anticancer drug discovery.