白介素-6（IL-6）是重要的细胞生长因子，能促进乳腺癌Ⅰ到Ⅳ期的发生发展，与癌症的转移、复发、耐药性等密切相关。胞外IL-6信号可激活JAK2激酶并磷酸化下游的STAT3蛋白，导致癌症。已知天然化合物Madindoline A（MDL-A）能与细胞表面的GP130蛋白直接结合并抑制STAT3的活化。本项目前期研究发现MDL-A通过抑制IL-6与GP130的结合，干扰IL-6/IL-6R/GP130三聚体二聚化为六聚体。因此，抑制IL-6/IL-6R/GP130二聚过程中的“蛋白-蛋白”相互作用(PPI)，阻止IL-6/STAT3信号通路的激活，可能是一种全新机制的治疗乳腺癌的方法。根据该机制，以MDL-A为先导物采用基于片段的药物设计法设计得一系列调控IL-6/IL-6R/GP130二聚化的PPI抑制剂，从而治疗肿瘤微环境介导的乳腺癌的转移、复发和耐药性，以期发现全新机制的抗肿瘤药物。

IL-6 is a critical growth factor, which may play a key role in the progression of breast cancer from stage I to stage IV cancer, typically associated with tumor cell metastasis, revival and resistance among breast cancer patients. Extracellular IL-6 can stimulate JAK2 kinase and then phosphorylated its downstream STAT3 protein causing cancer. Natural product Madindoline A (MDL-A) was known to interact with the extracellular domain of GP130 and thus to decrease the phosphorylation level of STAT3. Our early study found that MDL-A could inhibit the binding between IL-6 and GP130 and disrupt the dimerization process of IL-6/IL-6R/GP130. Thus, disabling the “Protein-Protein” interaction (PPI) during the dimerization process of IL-6/IL-6R/GP130 and then deactivating the IL-6/JAK2/STAT3 signaling pathway might be a new anti-breast cancer therapeutic direction. Our strategy is to use fragment-based computational approach to re-engineer the natural product compound, MDL-A, to make more potent and specific, synthetically-tractable small molecules to disrupt the IL-6/IL-6R/GP130 functional dimerization and ensuing STAT3 activation, thus leading to a new way to overcome breast cancer metastasis, recurrence and drug-resistance mediated by upregulated IL-6 in tumor microenvironment, for the discovery of new MOA anticancer drug.