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

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.

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。

本项目主要围绕以下三方面展开：1）完成了转录因子FoxM1 DNA结合域的原核表达制备以及FoxM1小分子抑制剂F1的合成与表征，成功建立了一种基于荧光共振能量转移实验（FRET）高通量筛选FoxM1抑制剂的新方法；2）研究了8-甲基鸟嘌呤修饰对G三链体结构稳定性和G三链体过氧化物酶催化活性的影响；3）对高等真菌、植物内生菌和民族药的次级代谢产物进行充分挖掘，建立了包含超过3000个结构新颖、功能多样的天然产物化合物库。在抗炎、抗肿瘤药物，小分子荧光探针，以及诸如FoxM1、PD-1/PD-L1和Mdm2/MdmX靶点抑制剂的筛选过程中，我们找到了一些活性较好的先导化合物,并对其调控机制进行深入研究。