基于Her-1抑制的旋覆花植物倍半萜类抗三阴性乳腺癌先导的发现、作用机制及体内活性评价

三阴性乳腺癌(TNBC)是目前最具侵略性和致命性的乳腺癌亚型，现有治疗均效果欠佳。表皮生长因子受体1(Her-1，EGFR)因在TNBC患者中表达高而有望成为新的治疗靶点。申请人前期针对TNBC细胞系，通过表型筛选首次发现三种秦岭旋覆花属植物的12个倍半萜精制组分具有抑制TNBC细胞增殖的活性，其中单体OABL和新二聚体DiA-1在亚微摩尔浓度下能选择性抑制TNBC细胞的增殖和迁移，以及选择性抑制Her-1激酶活性和磷酸化。本项目拟以靶向Her-1抑制TNBC为导向策略，对活性精制组分展开成分鉴定，通过多样性合成，筛选发现新先导化合物，分析构效关系；采用化学蛋白组学方法定量分析蛋白差异，鉴定先导分子的靶蛋白与阐明作用机制；研究其中1-2个活性分子在小鼠体内的抗TNBC功能，以期发现高效低毒的新型倍半萜药物先导。本项目对于天然药物的研发和机制研究具有重要意义。

Triple-negative breast cancer (TNBC) is the most aggressive and fatal breast cancer subtype. At present, chemotherapy, endocrine, and targeted therapies are ineffective. Epidermal growth factor receptor 1(Her-1 or EGFR) is expected to become a new drug therapeutic target due to its high expression in TNBC patients. In our previous studies, the cytotoxic-phenotypic screening for TNBC cells revealed for the first time that some refined SLs components of the Inula plants showed anti-proliferation activity against TNBC cells. A sesquiterpene OABL and dimer DiA-1 significantly inhibited the proliferation and migration of TNBC cells and EGFRTyr845 phosphorylation. This project hypothesizes that this type of sesquiterpenoids can inhibit TNBC by targeting the Her-1 signaling pathway. Now we are going to identify the new sesquiterpenoids by bioassay-guided isolation from three Inula species in Qinling Mountain. We will construct active compounds library and evaluate the structure-activity relationship through in vitro model-screening; Chemical proteomics method was used to quantitatively analyze protein differences, and then, the mechanism and in vivo evaluation on TNBC of 1-2 promising candidates from the screening will be finished. Hopefully, the lead compounds for TNBC therapy agents can be expected by this project, which is of great significance for the research of small molecular mechanisms and the development of new drugs.