以PLK1 PBD为靶点小分子抑制剂的筛选及抗肿瘤活性研究
发布时间：2018-11-02 12:26
【摘要】：采用荧光偏振高通量筛选的方法进行PLK1 PBD小分子抑制剂的筛选,对筛选出的阳性化合物F083-0063进行体外抗肿瘤活性研究,以期为寻找抗肿瘤药物提供先导化合物。模型筛选获取一个对PLK1 PBD抑制率较高的化合物F083-0063,其在10μg·mL~(-1)时的抑制率达(99.7±0.4)%;利用软件Graphpad Prism 5计算IC_(50)为1.9±0.1μmol·L~(-1);噻唑蓝比色法(MTT)研究该化合物对不同细胞系增殖的影响,结果显示F083-0063能抑制多种肿瘤细胞系的增殖;流式细胞仪检测发现,其能促进细胞凋亡且能导致细胞G2/M期阻滞;划痕实验测定F083-0063对细胞迁移的影响,结果显示其能抑制He La细胞迁移,在20μmol·L~(-1)时,迁移率低至(37.6±0.7)%。利用分子连接技术探讨化合物与PLK1 PBD结构域的亲和力,发现F083-0063与PLK1 PBD有较好的亲和性;免疫印迹法(Western blotting)检测显示F083-0063可以引发周期相关蛋白表达的增加。综上所述,化合物F083-0063有明显的抗肿瘤活性,并有望成为靶向PLK1 PBD的抗肿瘤先导化合物。
[Abstract]:PLK1 PBD small molecular inhibitors were screened by fluorescence polarization high throughput screening method. The antitumor activity of the selected positive compound F083-0063 was studied in vitro in order to provide a lead compound for searching for antitumor drugs. A compound F083-0063 with high inhibition rate to PLK1 PBD was obtained by model screening, and the inhibition rate of F083-0063was (99.7 卤0.4)% at 10 渭 g mL~ (-1), IC_ (50) was 1.9 卤0.1 渭 mol L ~ (-1) calculated by the software Graphpad Prism 5, and the inhibition rate of F083-0063 was (99.7 卤0.4)% at 10 渭 g mL~ (-1). The effect of F083-0063 on the proliferation of different cell lines was studied by (MTT). The results showed that F083-0063 could inhibit the proliferation of various tumor cell lines. Flow cytometry showed that it could promote cell apoptosis and induce G 2 / M phase arrest. The effect of F083-0063 on cell migration was determined by scratch test. The results showed that F083-0063 could inhibit the migration of He La cells, and the mobility was as low as (37.6 卤0.7)% at 20 渭 mol L ~ (-1). The affinity of F083-0063 to PLK1 PBD domain was studied by molecular binding technique. F083-0063 had good affinity with PLK1 PBD, and F083-0063 could induce the increase of cyclin-related protein expression by Western blot (Western blotting) assay. In conclusion, compound F083-0063 has obvious antitumor activity and is expected to be a leading antitumor compound targeting PLK1 PBD.
【作者单位】： 黑龙江中医药大学;中国医学科学院北京协和医学院医药生物技术研究所;
【基金】：国家自然科学基金面上项目资助(81370087)
【分类号】：R96;R94
，
本文编号：2306011
[Abstract]:PLK1 PBD small molecular inhibitors were screened by fluorescence polarization high throughput screening method. The antitumor activity of the selected positive compound F083-0063 was studied in vitro in order to provide a lead compound for searching for antitumor drugs. A compound F083-0063 with high inhibition rate to PLK1 PBD was obtained by model screening, and the inhibition rate of F083-0063was (99.7 卤0.4)% at 10 渭 g mL~ (-1), IC_ (50) was 1.9 卤0.1 渭 mol L ~ (-1) calculated by the software Graphpad Prism 5, and the inhibition rate of F083-0063 was (99.7 卤0.4)% at 10 渭 g mL~ (-1). The effect of F083-0063 on the proliferation of different cell lines was studied by (MTT). The results showed that F083-0063 could inhibit the proliferation of various tumor cell lines. Flow cytometry showed that it could promote cell apoptosis and induce G 2 / M phase arrest. The effect of F083-0063 on cell migration was determined by scratch test. The results showed that F083-0063 could inhibit the migration of He La cells, and the mobility was as low as (37.6 卤0.7)% at 20 渭 mol L ~ (-1). The affinity of F083-0063 to PLK1 PBD domain was studied by molecular binding technique. F083-0063 had good affinity with PLK1 PBD, and F083-0063 could induce the increase of cyclin-related protein expression by Western blot (Western blotting) assay. In conclusion, compound F083-0063 has obvious antitumor activity and is expected to be a leading antitumor compound targeting PLK1 PBD.
【作者单位】： 黑龙江中医药大学;中国医学科学院北京协和医学院医药生物技术研究所;
【基金】：国家自然科学基金面上项目资助(81370087)
【分类号】：R96;R94
，
本文编号：2306011
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