抗肿瘤激酶抑制剂靶点筛选与选择性评价体系
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摘要
目的:构建基于BaF3的激酶靶点等效基因细胞系文库,实现抗肿瘤激酶抑制剂精准靶点检测与选择性评价。方法:利用基因工程技术,以野生型鼠源B淋巴细胞(BaF3)为母板,将TEL/BCR/NPM/EML4等标签基因融合到目标基因的催化功能区域,诱导细胞脱离对IL-3生长因子的依赖,转而依赖外源转入的激酶的持续激活,如果化合物选择性抑制该种重组激酶的活性,就会导致相应细胞系发生凋亡。结果:已建成1 31个激酶靶点等效基因细胞系,涵盖了64种癌症相关激酶。结论:这种基于BaF3构建的等效基因细胞系文库具有遗传背景单一可控的特点,弥补了体外酶活实验假阳性高和癌症细胞系体系复杂的缺点,为研究和发现抗癌小分子药物的作用靶点,提供了高效易行的途径。
引文
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【4】"Ibrutinib selectively and irreversibly targets EGFR(L858R,De119)mutant but is moderately resistant to EGFR(T790M)mutant NSCLC Cells."Hong Wu,Aoli Wang,Wei Zhang,Beilei Wang,Cheng Chen,Wenchao Wang,Chen Hu,Zi Ye,Zheng Zhao,Li Wang,Xixiang Li,Kailin Yu,Juan Liu,Jiaxin Wu,Xiao-E Yan,Peng Zhao,Jinhua Wang,Chu Wang,Ellen L.Weisberg,Nathanael S.Gray,Cai-Hong Yun,Jing Liu*,Liang Chen*,Liu Qingsong*.Oncotarget,2015,Sep 5.DOI:10.18632/oncotarget.5182
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