癌症严重危害国民健康，防治任务艰巨。免疫疗法带来希望，但只对少数癌症有效，且易产生严重免疫性炎症，治疗条件苛刻费用高昂，尚不能普及和满足市场需求。传统化疗药物作用靶点单一易产生耐药性，因此，发现新型高效低毒的多靶点广谱型抗癌药物是一个突破口。HSP90抑制剂抑制单一蛋白（HSP90）形成多靶点干预癌症的效果，而HSP90C-端抑制剂较N-端抑制剂具有高选择性和低毒性等优点，是这类抗肿瘤药物研究的重要方向。然而，HSP90C-端抑制剂研究起步较晚，处于“发现难”阶段。鉴于此，项目基于前期发现新型HSP90C-端抑制剂VB4112，拟建立以VB4112为模板的HSP90C-端抑制剂药效团模型，指导设计合成天然HSP90C-端抑制剂关键活性基团/片段的嵌合物作为潜在HSP90C-端抑制剂并进行活性评价，以期发现优良抗肿瘤活性的HSP90C-端抑制剂，为新型抗肿瘤药物的研发奠定基础。

Cancer severely harms the health of Chinese people. It is a very arduous task to prevent and treat cancer in China. Immunotherapies bring hope to us, but it is curative to few cancers. Moreover, big risk of severe immune-inflammation together with harsh and high cost of medication treatment limit the application, and finally can not fulfill the market. Traditional chemotherapy drugs suffer from drug resistance because of these drugs interact with single targets. Thus, to find new type of broad-spectrum anti-cancer drug with high activity and low toxicity is a breakthrough point. HSP90 inhibitor exhibits a combinatorial attack on many cancer targets by interrupting only one protein (HSP90) to fight cancer. Among HSP90 inhibitors, HSP90 C-terminal inhibitor is more potential than HSP90 N-terminal inhibitor for its high selectivity to HSP90 and low toxicity, thereby becomes a significant task for the development of this kind of inhibitors. However, the research of HSP90 C-terminal inhibitor starts late, and is ceased on the period of “hard to discover”. On the basis of these information, and inspired by previous finding of novel HSP90 C-terminal inhibitor VB4112, in this project, the HSP90 C-terminal inhibitor pharmacophore model based on VB4112 is planned to build for directing the design and synthesis of the chimeras of key bioactive groups/fragments which are from natural HSP90 C-terminal inhibitors. Furthermore, the biological activities of resulting derivatives will be evaluated for discovery of the HSP90 C-terminal inhibitor with potent anti-cancer activity in this project. Last, the project will support the further innovation in novel type of anti-cancer drug development.