以顺铂为代表的铂类药物是目前临床肿瘤治疗中应用最广的一类药物，但其严重的副反应及肿瘤耐药大大限制其发展。RNA聚合酶I是一类全新的选择性抗肿瘤靶点，如选择性地对其抑制，可特异性地引起肿瘤细胞产生核仁应激，最终导致肿瘤细胞凋亡。本项目充分利用肿瘤细胞与正常细胞特征性差异，将RNA聚合酶I选择性抑制剂与铂药联合，设计合成新型铂类RNA聚合酶I选择性抑制剂，研究其构效关系，并探究其抗肿瘤作用机制，期望从分子水平上改变铂药作用方式，克服现有铂药缺陷。基于孪药设计和组合化学理念，本项目首先运用“Build-and-click”方法，构建新型铂类RNA聚合酶I抑制剂化合物库，并运用高通量筛选对其生物活性进行筛选、评价，得到活性化合物，探讨构效关系；同时，运用荧光后标记法结合分子生物学、细胞生物学等手段对该类化合物亚细胞定位及作用机制进行研究探讨，争取开发出高效、低毒的新型铂类RNA聚合酶I抑制剂。

Platinum-based anticancer drugs, represented by cisplatin, are the most widely used chemotherapy agents in clinical oncology. However, the severe side effects, as well as drug resistance extremely restrict the developments of platinum-based agents. RNA polymerase I (RNA Pol I) is an emerging selective target for cancer therapy. Selective inhibition of RNA Pol I can significantly trigger nucleolar stress in cancer cells, and ultimately induce apoptosis. By utilizing the characterized differences between normal cells and cancer cells, we combine the advantages of RNA Pol I inhibitors and platinum drugs to develop novel platinum-Pol I inhibitors for cancer treatments. The ultimate goal for this project is to overcome the clinical drawbacks of current platinum drugs by altering their acting mechanism at the molecular level. A novel library of platinum-based RNA Pol I inhibitors will be developed using a build-and-click approach based on twin drug design and combinatorial chemistry. In order to obtain structure-activity relationships and active “warheads”, the library will be subsequently subjected to biological evaluation using various assays. For the cellular imaging and mechanistic studies, a fluorescent post-labeling method will be established and combined with molecular and cellular biology methods. Developing and understanding of novel platinum-based Pol I selective inhibitors may ultimately lead to the more efficient and less toxic platinum agents for future cancer therapy.