Discovery of thiazolidin-4-one urea analogues as novel multikinase inhibitors that potently inhibit FLT3 and VEGFR2.
Discovery of thiazolidin-4-one urea analogues as novel multikinase inhibitors that potently inhibit FLT3 and VEGFR2.
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DOI：
10.1016/j.bmc.2019.03.049
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发表时间：
2019-03
影响因子：
3.5
通讯作者：
Baohui Qi;Xingwei Xu;Ying Yang;Yuting Zhou;Tao Chen;Guowei Gong;Xupeng Yue;Xingwei Xu;Li-hong Hu;Huan He
中科院分区：
文献类型：
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作者：
Baohui Qi;Xingwei Xu;Ying Yang;Yuting Zhou;Tao Chen;Guowei Gong;Xupeng Yue;Xingwei Xu;Li-hong Hu;Huan He
设计、合成了一系列新型噻唑烷-4-酮脲类似物，并进行了生物活性评价。通过分子模拟研究，考察了支架不同位置的构效关系，并分析了其结合模式。化合物17 b对A549和HT-29细胞的IC_（50）分别为0.65 μM和0.11 μM。激酶谱的结果表明，化合物17 bis是一种多激酶抑制剂，其有效地抑制FLT 3（IC 50 = 8.6 nM）和VEGFR 2（IC 50 = 18.7 nM）。实时活细胞成像的结果表明，化合物17 b以时间和剂量依赖性方式显示出优异的针对HT-29癌细胞的细胞毒性和抗增殖活性，其显著强于卡博替尼。此外，体外抗肿瘤活性与诱导癌细胞凋亡和抑制癌细胞迁移有关。
A series of novel thiazolidine-4-one urea analogues were designed, synthesized and biologically evaluated. The structure-activity relationship (SAR) at several positions of the scaffolds was investigated and its binding mode was analyzed by molecular modeling studies. Compound17bproved to be the most potent one, and IC50values against A549 and HT-29 cancer cell lines were 0.65 μM and 0.11 μM, respectively. The results of kinase profile demonstrated that compound17bis a multikinase inhibitor that potently inhibits FLT3 (IC50= 8.6 nM) and VEGFR2 (IC50= 18.7 nM). The results of real-time live-cell imaging indicated that compound17bshowed excellent cytotoxicity and anti-proliferative activity against HT-29 cancer cells in a time- and dose-dependent manner, which was significantly potent than that of Cabozantinib. In addition,in vitroantitumor activity was associated with inducing cancer cell apoptosis and suppression of cancer cell migration.