海洋天然产物Grincamycin B的靶标鉴定、确证及抗肿瘤机制研究

海洋天然产物是药物研发的新宝库和重要来源。Grincamycin B（GCN-B）是来源于海洋放线菌的角环素类次级代谢产物，其母核两侧含两条寡糖侧链，结构新颖，初步鉴定具有良好的抗肿瘤活性。但是，此类化合物的生物靶标及作用机制研究尚不清楚，限制了其进一步的转化和应用。我们前期研究发现，GCN-B可以选择性地诱导血液系统肿瘤细胞发生凋亡。综合利用化学生物学、转录组学以及生物化学等多学科手段初步鉴定，GCN-B可诱导细胞产生活性氧，改变胞内氧化还原平衡，并在体外抑制异柠檬酸脱氢酶IDH1的酶活。本研究旨在此基础上，明确GCN-B与所鉴定的IDH1分子靶标之间的结合模式和调控机理；确证GCN-B的分子靶标与抗肿瘤活性的相关性；并阐明靶标与肿瘤发生发展以及预后之间的关系，为Grincamycin类天然产物在抗肿瘤领域的进一步转化应用奠定理论基础。

Marine natural products are new treasure and important resources of drug discovery. Gricamycin B with a potential anti-tumor activity is a marine-originated Angucycline derivative with a core structure and oligosaccharide chain on both sides. Its complex structure and little knowledge of its molecular target and mechanism limited further translational study. In our preliminary study, We have confirmed that GCN-B could induce apoptosis of several tumor cell cells，especially of acute myeloid leukemia, in a dose-dependent manner.By using different techniques and tools from multi-disciplinary science fields, we identified that GCN-B was able to induce reactive oxygen species, disrupt reductive balance and inhibit the activity of isocitrate dehydrogenase 1(IDH1) in vitro. In this project, we will further identify and validate the direct molecular target of GCN-B, characterize its binding mode, explore the relationship between the target and the biological effect, and evaluate whether the GCN compounds could be novel potential leading compounds that be used for treatment of AML and other malignancies.