木豆源茋类化合物及其衍生物靶向PKM2抗癌的作用和机制研究

Stilbenoids have been proved to have great potential in development of anticancer drug, while Pyruvate kinase M2 (PKM2) has been shown as an important target for anticancer drugs due to its key roles in metabolism regulation of tumor cells. Cajanus cajan, which mainly distributed in provinces such as Guizhou and Yunnan in China, is a rich source of stilbenoids. Previously we found that stilbenoids isolated from Yunnan Cajanus cajan potentially target PKM2 to inhibit the growth of tumor cells. On these basis, here we plan to isolate stilbenoids both from Guizhou and Yunnan Cajanus cajan species, and further construct a library of stilbenoid derivatives derived from stilbenoids showing PKM2-targeting and anticancer activities under the guide of molecular docking. The isolated stilbenoids and the derivative library would be screened for PKM2-targeting and anticancer activities. For the active stilbenoids, in addition to the analysis of relationship between their structure and anticancer function, further studies would be performed to reveal the mechanism of their anticancer activities by comparison of transcriptome, protein expression, PKM2 activity and apoptosis of cancer cells with and without treatment of stilbenoids. This study would provide new lead molecules and scientific basis for the development of PKM2-targeting anticancer drugs with high-efficiency and low-toxicity. Furthermore, it is important for exploration of local medicinal herb resources in China.

茋类化合物被证实具有显著的抗癌潜力，而M2型丙酮酸激酶（PKM2）参与调控癌细胞代谢，被发现是一个新型重要抗癌药物靶标。分布于我国贵州和云南等省份的木豆是重要的茋类化合物来源。我们前期研究发现，云南产木豆中茋类化合物具有靶向PKM2抑制肿瘤细胞增殖的潜力。本项目拟在此基础上，富集分离贵州和云南产木豆中靶向PKM2和抑制肿瘤细胞的茋类化合物，并在分子对接指导下，建立茋类衍生物库，筛选确定具有PKM2活性抑制作用的茋类化合物，并揭示其构效关系。进而通过检测活性茋类化合物作用后，癌细胞的转录组学分析、蛋白表达、PKM2活性和细胞凋亡特征分子变化，研究茋类化合物靶向PKM2抗癌的作用机制。本项目的完成将有助于开发我国地方药用植物资源，发现能显著抑制PKM2蛋白的抗癌先导分子，并为研制特异靶向PKM2蛋白的高效低毒抗癌药物提供理论指导。

茋类化合物白藜芦醇、紫檀茋和combretasatin A-4都被报道具有显著的抗癌活性。木豆（Cajanus cajan）主要分布于我国云南、贵州等省份，具有重要的药用价值，富含活性茋类化合物。本项目完成了贵州产木豆及云南产木豆的提取分离，共分离得到76个化合物，得到2个新的茋类化合物，2个新的木脂素和1个新的黄酮苷。对部分化合物进行了肿瘤细胞系筛选，并阐明了茋类化合物(3-methoxy-5-hydroxy-stilbene)通过作用于BTK介导的KRAS/HDAC1/EP300/PEBP1轴诱导Raji细胞凋亡。除此之外，对从贵州产木豆中分到的化合物进行了α-葡萄糖苷酶抑制活性评价并讨论了其构效关系。该项目的研究结果为木豆资源的开发利用奠定了科学基础。