肿瘤细胞耐药性与细胞内ERK1靶点的激活存在密切关系。已有相关临床报导大环内酯类抗生素具有抑制肿瘤多药耐药性的特点。本课题组前期研究发现筛选的3株具有抗肿瘤活性菌株的次级代谢产物萃取物和其中的大环内酯类化合物，有显著的抗肿瘤活性,并通过“分子对接”和细胞凋亡实验证明了其中的大环内酯类化合物是潜在的ERK1抑制剂。为了更快速的获得大量新的大环内酯类ERK1抑制剂，本课题组拟应用“配体垂钓”为前期技术指导，采用“活性追踪”和“分子对接”的协同作用，多重导向分离微生物代谢产物中的大环内酯类化合物。结合计算机辅助药物设计筛选出与ERK1受体结合能力较高的潜在抑制剂后，进一步测试这些化合物的ERK1受体抑制活性和抗肿瘤多药耐药活性，优选出结构新颖的具有良好活性的先导化合物，并为进一步研究ERK1抑制剂在抑制肿瘤多药耐药中的作用机制和通路提供思路。

Recently, ERK1 has been found to play an important role in the multidrug resistance of human tumor activity. Moreover, it is proven that macrocyclic lactone compounds from microbial metabolites have the ability to resist human tumor activity. In our previous study, extracts and compounds from three microbial metabolites were found to have significant anti-tumor activity, besides, macrocyclic lactone are found to be potential ERK1 inhibitor by docking and cell apoptosis assay. We infer that the multidrug resistance of human tumor activity may be caused by the inhibitor of ERK1 inhibitor. Based on docking theory, we plan to find the types of macrocyclic lactone compounds by the ligand fishing techniques and bioassay-guided methods (multi-guided isolation). Using docking technology to screen these isolated compounds to find potential ERK1 inhibitor. Furthermore, the ERK1 inhibitor activity and multidrug resistance of human tumor activity of these compounds, in order to discover the structure-activity relationship of these compounds. In addition, the mechanism and the binding sites of the ERK1 inhibitor will be discussed, which will make contribution to the screening of the leading compounds which can be further investigated regarding the pathways and the mechanisms of the multidrug resistance of human tumor activity.