靶向转录因子FOXM1的抑制剂设计、筛选及其对转录机制调控的研究

项目名称： 靶向转录因子FOXM1的抑制剂设计、筛选及其对转录机制调控的研究

项目编号： No.21502239

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 环境科学、安全科学

项目作者： 黄蓉

作者单位： 中南民族大学

项目金额： 21万元

中文摘要： 转录因子FOXM1在细胞增殖过程和细胞周期进程中起重要的作用，且被证实与多种致瘤信号途径密切相关。以FOXM1蛋白为靶点的药物设计开发成为了癌症治疗研究的热点。目前被广泛研究的FOXM1蛋白抑制剂存在着结合力较弱、作用位点较多和毒副作用较大等问题。本项目拟通过高通量药物筛选和先导化合物衍生修饰，找寻FOXM1的高效抑制剂并深入研究其对FOXM1转录调控机制的影响。我们拟在先导化合物上引入光交联基团以共价结合方式增强其对FOXM1转录活性的抑制；并且设计抑制剂-核酸适配子复合物来提高其靶向作用。同时，我们拟建立以民族药物资源为基础的高通量筛选模型以筛选出靶向FOXM1蛋白的新型民族药物。

中文关键词： 转录因子；FOXM1；抑制剂；转录机制

英文摘要： Transcriptional Factor FOXM1 plays a key role in cell proliferation and cell cycle process. Aberrant overexpression of FOXM1 is closely related to oncogenesis and progression of many human cancers. The design and development of FOXM1-targeting drugs has become the hot spot of cancer treatment research. Those FOXM1 inhibitors which are extensively studied have some limitations, such as weak binding, multiple action sites and side effects. In this project, we try to develop efficient inhibitors of FOXM1 and investigate their functions on transcriptional regulatory mechanism of FOXM1. We will introduce photo-crosslinking group onto the lead compound to enhance its inhibition towards FOXM1 transcriptional activity through covalent binding. Also, we will design inhibitor-aptamer complex to improve selective targeting. In addition, we will establish a high-throughput screening model on the basis of natural ethical medicine resources, to screen out novel FOXM1-targeting drugs.

英文关键词： Transcriptional Factor;FOXM1;Inhibitors;Transcriptional Mechanism