Aurovertins抗三阴乳腺癌构效关系及抗转移作用研究

Triple-negative breast cancer (TNBC), defined by extremely low or lack of estrogen receptor, progesterone receptor and HER2 receptors, represents a distinct subtype of breast cancer and accounts for 15% of all breast cancers. It is urgent and useful to discovery anti-TNBC drugs, as there is no good clinic drug for treatment of TNBC at this time.. In premilary experiments, aurovertins was found to display potent and selective inhibitory activity against TNBC. Furthermore, aurovertins also display the inhibitory activity against metastasis of TNBC. The project will use bioinformational and chemical analysis to screen fungi with capacity of producing aurovertin analogs. Then the targeted isolation directed by and chemical feature provides aurovertins analogs with structural diversity. After bioassay and structure analysis, the structure and activity relationship will be revealed, which can direct the structure modification of aurovertins. In addition, the project will confirm the anti-metastsis activity of aurovertins against TNBC, and reveal the mechanism of their anti-metastsis role. The implementation of this project can provide new lead compounds for treatment of TNBC, which has a positive meaning for the health of women.

三阴型乳腺癌（TNBC）指的是雌激素受体、孕激素受体和人类表皮生长因子受体-2均为阴性表达的乳腺癌亚型，约占所有乳腺癌患者的15%左右。TNBC预后易发生转移和复发，而且对于TNBC还缺乏有效可靠的治疗药物。. 前期研究发现aurovertins对TNBC具有很强的选择性抑制作用，还发现aurovertins还具有抗转移作用。本项目拟在前期基础上采用生物信息学和化学分析筛选出能代谢aurovertins类似物能力的真菌。然后采用化学跟踪指导下分离获得结构多样性的aurovertins类似物。采用化学与生物相结合的方法对aurovertins类似物进行抗TNBC活性评价及构效关系研究，为aurovertins的结构优化提供指导。然后对获得的化合物进行抗转移作用及机制研究。本项目的实施可以为TNBC的治疗提供先导化合物，对妇女的健康有着积极的意义。

三阴型乳腺癌（TNBC）指的是雌激素受体、孕激素受体和人类表皮生长因子受体-2均为阴性表达的乳腺癌亚型，约占所有乳腺癌患者的15%左右。TNBC预后易发生转移和复发，而且对于TNBC还缺乏有效可靠的治疗药物。. 本项目通过基因挖掘发现Metarhizium robertsii ARSEF 2575、Metarhizium anisoliae ARSEF 23、Aspergillus terrus NIH2624中具有代谢aurovertin类化合物的能力。采用LC-DAD进行分离指导，对菌丝体中的aurovertins进行了定向分离，完成了Calcarisporium arbuscula，Metarhizium anisopliae中的化合物分离，获得了19个aurovertins类化合物，其中4个为新化合物。活性评价表明部分aurovertins类似物对TNBC均具有很强的特异性抑制作用。体内外实验表明aurovertin B对TNBC具有很强的抗转移作用，并初步阐明了其抗转移与DUSP1蛋白表达的上调有关。本项目的实施为TNBC的治疗提供先导化合物，对妇女的健康有着积极的意义。