STAT3 的组成性激活有助于肿瘤的发展和转移，使其成为癌症治疗的有希望的靶点。 (1R,4R,5S)-10-羟基-9-甲氧基-8,11-二甲基-3-(萘-2-基甲基)-1,2,3,4,5,6-六氢-1,5-表氨基苯并[d]阿佐辛-4-甲腈 (DH_31) 是海洋天然产物雷尼尔霉素 T 的新衍生物，对 H292 和 H460 细胞表现出有效的活性，IC50 值分别为 5.54 ± 1.04 µM 和 2.9 ± 0.58 µM。构效关系（SAR）分析表明，在C环上添加带有甲基连接基的萘环，在E环上添加羟基可增强DH_31的细胞毒作用。在 1-2.5 µM 浓度下，DH_31 显着抑制 EMT 表型（例如迁移）并使细胞对失巢凋亡敏感。与 mRNA 和蛋白质水平上 ZO1 的上调以及 Snail、Slug、N-cadherin 和 Vimentin 的下调一致，计算机预测将 STAT3 确定为靶标，并通过蛋白质分析进行验证，表明 DH_31 通过泛素显着降低 STAT3 水平。蛋白酶体降解。免疫荧光和蛋白质印迹分析证实 DH_31 显着降低 STAT3 和 EMT 标记物。此外，分子对接表明 STAT3 的 DNA 结合域中 DH_31 的氰基和 Cys-468 之间存在共价相互作用（结合亲和力 = -7.630 kcal/mol），导致此后不稳定。总之，DH_31，一种新型 RT 衍生物，显示出作为 STAT3 靶向药物的潜力，可显着有助于理解新靶向治疗的开发。

Constitutive activation of STAT3 contributes to tumor development and metastasis, making it a promising target for cancer therapy. (1R,4R,5S)-10-hydroxy-9-methoxy-8,11-dimethyl-3-(naphthalen-2-ylmethyl)-1,2,3,4,5,6-hexahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile, DH_31, a new derivative of the marine natural product Renieramycin T, showed potent activity against H292 and H460 cells, with IC50 values of 5.54 ± 1.04 µM and 2.9 ± 0.58 µM, respectively. Structure-activity relationship (SAR) analysis suggests that adding a naphthalene ring with methyl linkers to ring C and a hydroxyl group to ring E enhances the cytotoxic effect of DH_31. At 1-2.5 µM, DH_31 significantly inhibited EMT phenotypes such as migration, and sensitized cells to anoikis. Consistent with the upregulation of ZO1 and the downregulation of Snail, Slug, N-cadherin, and Vimentin at both mRNA and protein levels, in silico prediction identified STAT3 as a target, validated by protein analysis showing that DH_31 significantly decreases STAT3 levels through ubiquitin-proteasomal degradation. Immunofluorescence and Western blot analysis confirmed that DH_31 significantly decreased STAT3 and EMT markers. Additionally, molecular docking suggests a covalent interaction between the cyano group of DH_31 and Cys-468 in the DNA-binding domain of STAT3 (binding affinity = -7.630 kcal/mol), leading to destabilization thereafter. In conclusion, DH_31, a novel RT derivative, demonstrates potential as a STAT3-targeting drug that significantly contribute to understanding of the development of new targeted therapy.