新型抗胰腺癌大环内酰胺先导化合物发现、构效关系及作用机制研究

Pancreatic cancer is a highly malignant tumor of the digestive system that is extremely difficult to diagnose and treat. In recent years, the incidence of pancreatic cancer continues to grow, leading to serious challenges in the development of new drugs for pancreatic cancer. Studies have shown that STAT3 is an important target for the development of anti-pancreatic cancer drugs. Natural products and their derivatives are important sources of new drug research and development. We used the STAT3 targeted screening system to obtain a macrocyclic lactam, trienomycin A, a natural small molecule with STAT3 transcriptional repression activity. Preliminary experimental results show that the compound significantly inhibits the proliferation and migration of pancreatic cancer cells; and significantly inhibits the phosphorylation of STAT3. However, it is unclear its anti-pancreatic cancer activity in vivo and molecular mechanisms. This project assumes that Trienomycin A will inhibit the progression of pancreatic cancer by targeting the STAT3 signaling pathway. Trienomycin A analogs were identified from the cultures of Streptomyces sp., and modifications of trienomycin A were performed based on diversity synthetic strategies to evaluate anti-pancreatic cancer activity in vitro and in vivo. The structure-activity relationship (SAR) will be elucidated. We are to investigate novel functions and mechanisms by which Trienomycin A inhibits pancreatic cancer growth and metastasis by targeting STAT3. Finally, new antipancreatic cancer candidate compounds with high efficiency and low toxicity will be identified. This project is of great significance for the research of small molecule mechanism and research and development of new drug.

胰腺癌是高度恶性的消化系统肿瘤，发病率持续增长，严重危害人们健康。STAT3是胰腺癌新药研发的重要靶点。天然产物及其衍生物是新药研发的重要源泉。申请者通过靶向STAT3筛选系统得到天然小分子大环内酰胺Trienomycin A(自编号HQ-4)。前期研究表明，该化合物显著抑制胰腺癌细胞增殖和迁移，并抑制STAT3转录活性和磷酸化。但尚不清楚其体内抗胰腺癌活性和分子机制。本项目假设Trienomycin A通过靶向STAT3信号通路抑制胰腺癌的发展。拟研究一株放线菌Streptomyces sp.的发酵产物和基于多样性改造策略合成Trienomycin A 衍生物，评价体内外抗胰腺癌活性，并阐明构效关系；研究Trienomycin A及高活性化合物通过靶向STAT3抑制胰腺癌生长和转移的新功能和新机制，以发现高效低毒的候选化合物。本项目对于小分子机制研究和新药研发具有重要意义。

胰腺癌是一种高度恶性的消化系统肿瘤，诊断和治疗难度很大。信号转导子和转录激活子-3（STAT3）在许多人类癌症中持续激活，促进肿瘤的发展和进展。我们确定了天然产物三烯霉素A（TA），一种安莎霉素类抗生素，作为STAT3途径的潜在抑制剂，具有强的抗胰腺癌活性。然而，人们关于TA对胰腺癌的影响知之甚少，TA的潜在分子机制也不清楚。本研究所取得的主要结果如下：.1）菌株H2S5发酵物中分离鉴定20多个代谢产物；2) 衍生合成系列三烯霉素衍生物；3) 探讨了构效关系；4)三烯霉素A作为新型 STAT3 途径抑制剂体内体外都显示出显著抗胰腺癌效果。三烯霉素A直接与STAT3结合并抑制STAT3（Tyr705）磷酸化，从而抑制STAT3途径。三烯霉素A还抑制胰腺癌细胞系的集落形成、增殖、迁移和侵袭。三烯霉素A也显著抑制了体内胰腺肿瘤的生长。重要的是，三烯霉素A在体内的有效剂量下没有表现出明显的毒性。总的来说，三烯霉素A通过抑制胰腺癌中STAT3的激活而发挥抗肿瘤活性。本研究首次揭示TA高活性分子通过靶向STAT3信号通路抑制胰腺癌的生长和转移的新机制，属于一类全新的STAT3抑制剂，有望为安沙霉素类化合物作为治疗胰腺癌的新候选药物开发提供重要实验依据和新思路。