基于生物亲和探针精准发现泽兰属三种中药中MAA型新颖STAT3特异性抑制剂及分子靶向抗三阴性乳腺癌研究

STAT3为三阴性乳腺癌(TNBC)颇具前景的精准化疗新靶标。项目组前期研究表明：从泽兰属中药倍半萜内酯(SL)中，发现迈克尔受体分子(MAA)型STAT3抑制剂，颇具研究前景。项目组认为：一、SL中“α-β不饱和羰基”能烷化修饰STAT3蛋白SH2或DBD域关键半胱氨酸，抑制STAT3活性；二、泽兰属中药中MAA型STAT3抑制剂可能具有分子靶向抗TNBC活性。本项目基于抑制剂分子机制假说，拟选生物亲和探针，构建泽兰属中药中MAA型STAT3特异性抑制剂精准发现技术，筛选高效抑制剂；从STAT3可能被定点烷化修饰角度，研究抑制剂分子作用机制；综合评估抑制剂分子靶向抗TNBC活性。精准发现技术的构建，将有益于改良、优化中药新颖、活性成分筛选的传统模式；抑制剂分子作用机制的阐明及综合抗TNBC活性研究，也将是TNBC精准治疗的有益探索，并将为新型分子靶向抗TNBC药物的理性设计提供科学依据。

STAT3 is a promising new target for triple-negative breast cancer (TNBC) precise chemotherapy. The preliminary study of our group showed that there is a considerable research prospect on discovery Michael addition acceptor (MAA) type STAT3 inhibitor from sesquiterpene lactone (SL) in Eupatorium L. traditional Chinese medicine (TCM). Our group believes that: the first, MAA-type STAT3 inhibitor could alkylation modify key cysteine on STAT3 SH2 or DBD domain to produce function, through its “α-β unsaturated carbonyl”; the second, MAA-type STAT3 inhibitor in Eupatorium L. TCM probably has molecular tageted anti-TNBC activity. This project is based on the molecular mechanism hypothesis of inhibitor, we select biological affinity probe to establish a precise discovery technology of MAA-type STAT3 specific inhibitor in Eupatorium L. TCM, and to screen efficient inhibitors; From the point that STAT3 may be site-specific alkylation modified, to study the molecular mechanism of MAA-type STAT3 inhibitor, comprehensively study its molecular tageted anti-TNBC activity. The build of precise discovery technology will be beneficial to improve traditional screening model of TCM active ingredients; the revealing of molecular mechanism and the comprehensive assessment of anti-TNBC activity of MAA-type STAT3 inhibitor, will be a useful exploration for TNBC precise therapy, and also will provide a scientific basis to rational design novel molecular tageted anti-TNBC drug.