以sorcin蛋白为靶点的天然产物小分子的发现、优化及其抗胰腺癌干细胞活性研究

Metastasis and reccurence are the biggest troubles for therapy of pancreatic cancer. Pancreactic cancer stem cells (PCSCs) are considered to be the root of metastasis and reccurence. However, the clinical used drugs can not target PCSCs. The main method for discovery of anti-PCSCs compounds is random screening. The rate for discovery PCSCs is very low. On the base of previous research, we firstly revealed that sorcin was the key protein for regulation of PCSCs and found four kinds of natural products targeting sorcin could ablate PCSCs. This project plan to study the chemical constitute of six plants and perform chemical modification on natural product to optimize their druggability, which will reveal the relationships of structure-ability of binding sorcin protein-activity against PCSCs.These compounds with high activity against PCSCs will be further investigated for identification of their target of sorcin protein, activity against PCSCs, and pharmacodynamic study in vivo.These studies are supposed to find 3-5 compounds with high activity against PCSCs in vivo. The most active compound will be co-crystalized with sorcin protein. Key binding sites with sorcin protein will be revealed. The project will provide small molecule drug for study of the key protein and signal pathway for regulating PCSCs, provide guidance for rational design of anti-PCSCs compounds, and provide base for solving the metastasis and reccurence problems for pancreatic cancer treatment.

胰腺癌治疗的最大难题是转移和复发，胰腺癌干细胞（PCSCs）是胰腺癌转移和复发的根源，临床药物不能靶向PCSCs，抗PCSCs化合物的主要发现途径是随机筛选，成功率低。前期首次发现sorcin蛋白是调控PCSCs的关键蛋白，发现靶向sorcin蛋白的四个结构类型天然产物能选择性清除PCSCs。本项目拟对富含四个结构类型天然产物的六种植物进行化学成分研究，针对化合物存在的问题结构修饰，揭示结构-sorcin蛋白结合-抗PCSCs活性三重关系；抗PCSCs活性高的化合物进行体内sorcin靶点验证、靶向PCSCs活性确认及药效评价，期望发现3–5个可选择性清除PCSCs且体内药效显著的化合物；最优化合物与sorcin蛋白共晶培养，研究与sorcin蛋白结合位点。为研究调控PCSCs的关键蛋白和通路提供小分子工具药物，为合理设计抗PCSCs化合物提供指导，为解决胰腺癌转移和复发难题奠定物质基础。

胰腺癌是最恶性、预后最差、死亡率最高的一种癌症类型。高死亡率主要是由于放疗和化疗后的复发和转移，胰腺癌干细胞（PCSCs）被认为是复发和转移的根源。靶向PCSCs可能大大降低复发和转移的几率。然而，目前使用的药物不能选择性清除PCSCs。因此，迫切需要发现PCSCs的新靶点并开发消除PCSCs的治疗药物，以克服当前胰腺癌症治疗的挑战。我们揭示了sorcin如何促进PCSCs进展的机制，并筛选发现celastrol能直接与sorcin结合、消除PCSCs并探索了其作用机制。我们发现sorcin与胰腺癌症的生存率和肿瘤分期呈正相关，并在维持PCSCs中发挥重要作用。sorcin与细胞质中的PAX5相互作用，抑制PAX5的细胞核易位，从而降低FBXL12蛋白的表达，然后降低ALDH1A1的泛素化，导致PCSCs的维持和积累。筛选天然产物库发现，celastrol可以与sorcin结合，并影响sorcin与PAX5的相互作用，这提高了PAX5的核易位、FBXL12蛋白的表达和ALDH1A1的泛素化，从而清除PCSCs。Celastrol可在体外和体内清除PCSCs。这些发现通过调节PAX5的细胞核易位和FBXL12的表达，将sorcin与ALDH1A1联系起来，并揭示靶向sorcin-PAX5相互作用可能成为一种治疗胰腺癌的新策略，为发现新型抗胰腺癌药物奠定基础。.发表第一或通讯作者论文研究论文8篇，包括药物化学领域顶级期刊J Med Chem 1篇，J Hemotol Oncol 1篇，Eur J Med Chem 2篇；指导毕业硕士研究生4名。