一种用于筛选具有抗肿瘤活性的沙利度胺衍生物分子平台的建立

摘要

目的：建立用于筛选具有抗肿瘤活性的沙利度胺衍生物的分子平台。方法从人胎肝cDNA文库中分别扩增cereblon（CRBN）和Ikaros家族锌指蛋白1（Ikaros family zinc finger protein 1，IKZF1） cDNA，并将其克隆入pXJ40-myc和pcDNA3-FLAG载体中，将其转染293T细胞，通过检测沙利度胺及其衍生物对CRBN和IKZF1蛋白相互作用的改变，间接反映其在肿瘤抑制中的作用。结果 CRBN和IKZF1在293T细胞中均得到表达，沙利度胺及其两个衍生物可显著增强CRBN和IKZF1的结合。结论成功建立了用于筛选具有抗肿瘤活性的沙利度胺衍生物分子平台，初步发现2个沙利度胺衍生物可显著增强CRBN和IKZF1的结合，提示其具有潜在的抗癌活性。%objective To establish a molecular platform for screening thalidomide derivatives with potential high anti-tumor activities. Methods Human cereblon(CRBN) and Ikaros family zinc finger protein 1(IKZF1) cDNA were amplified and cloned into pXJ40-myc and pcDNA3-FLAG vectors respectively. Then the two constructs were transfected into 293T cells and the anti-tumor activities of thalidomide and its derivatives were reflected by their effects on the binding between CRBN and IKZF1 proteins. Results Both CRBN and IKZF1 were successfully expressed in 293T cells. Thalidomide and two of its derivatives were found to enhance the interaction between CRBN and IKZF1 significantly. Conclusion A molecular platform was successfully established for screening thalidomide derivatives with potential high anti-tumor activities and two thalidomide derivatives could potentiate the binding between CRBN and IKZF1, suggesting that they possess potential anti-tumor activities.