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 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.

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。

菊科泽兰属中药富含倍半萜内酯，其为一类天然迈克尔反应受体分子(MAA)，MAA型倍半萜内酯具有烷化修饰抑制STAT3的潜能，MAA型STAT3抑制剂亦具有良好的抗三阴性乳腺癌(TNBC)前景。项目组建立了泽兰属中药中MAA型STAT3特异性抑制剂精准发现技术，基于精准发现技术导向，对泽兰属：野马追、大麻叶泽兰、华泽兰三种中药进行了较系统的化学成分研究，共获得了29个MAA型倍半萜内酯，其中新化合物5个，发现了两个MAA型STAT3特异性抑制剂：Eupalinolide J、Eucannabinolide，深入、系统研究了两个抑制剂抗TNBC活性及分子机制，预示其为有前景的抗TNBC先导物。制备得到了两个倍半萜内酯组合物型抗TNBC有效部位，对其进行了较系统抗TNBC活性及机制研究，其安全有效、稳定可控，具有一定的药物应用开发前景。本研究建立的精准发现技术，能提高获得高效价特异性STAT3抑制剂的几率；MAA型STAT3抑制剂抗TNBC亦是中药有效成分精准治疗TNBC的有益探索；抑制剂分子机制的初步阐明亦为该类型抗TNBC前药的理性设计提供了科学依据。