文献类型：期刊文献

英文题名：Discovery of Hirsutellones as Nucleolin-Targeting Natural Macrocycles for Triple-Negative Breast Cancer Treatment

作者：Gong, Lizhi[1];Yang, Jin[1];Guo, Jiacheng[1];Gao, Zhen[2];Gao, Ning[1,6];Wu, Yuzhen[1];Xiong, Pengyu[1];Xin, Xiujuan[1];Li, Baoli[3];Li, Jian[3,4,5];Wei, Jinlian[4];An, Faliang[1,7]

机构：[1]East China Univ Sci & Technol, Sch Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China;[3]Hainan Univ, Engn Res Ctr Drug Screening & Evaluat, Sch Pharmaceut Sci, Key Lab Trop Biol Resources,Minist Educ & Hainan, Haikou 570228, Peoples R China;[4]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Frontiers Sci Ctr Mat Biol & Dynam Chem, State Key Lab Bioreactor Engn,Sch Pharm, Shanghai 200237, Peoples R China;[5]Shihezi Univ, Sch Pharm, Key Lab Xinjiang Phytomed Resource & Utilizat, Minist Educ, Shihezi 832003, Peoples R China;[6]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China;[7]Marine Biomed Sci & Technol Innovat Platform Lin G, 4, Lane 218, Haiji Sixth Rd, Shanghai 201306, Peoples R China

年份：2026

卷号：69

期号：13

起止页码：15339

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;Scopus(收录号：2-s2.0-105044344405);WOS:【SCI-EXPANDED(收录号:WOS:001794756600001)】；

基金：This work was financially supported by the Shanghai Natural Science Foundation (25ZR1401076), the Innovative Drug Research and Development-National Science and Technology Major Project (2025ZD1803000), the National Key R&D Program of China (2023YFA0914102), and the Shanghai Collaborative Innovation Centre for Biomanufacturing Technology. This work was also supported by the Open Research Fund Program of State Key Laboratory of Bioreactor Engineering and Shanghai Collaborative Innovation Centre for Biomanufacturing Technology. We sincerely thank Prof. Junsong Wang (Nanjing University of Science and Technology) for his valuable support in this research.

语种：英文

摘要：Triple-negative breast cancer (TNBC) remains a major clinical challenge due to its aggressive behavior, high metastatic potential, and limited therapeutic options, as current treatments often constrained by resistance and toxicity. Here, ten structurally distinct macrocyclic alkaloids were discovered from Didymella sp. Compounds 1 and 2 possessed the 13-membered macrocyclic ring alongside the novel spiro junction at C-3/C-18. Among them, phomapyrrolidone A (Ppd A) was the most active compound in the series, showing the lowest IC50 values and favorable selectivity toward TNBC cells. Integrated proteomic profiling, bioinformatic analysis, and clinical tissue validation converged on nucleolin (NCL) as a direct and functionally relevant target. Mechanistically, Ppd A binds to the Gln558 residue of NCL, disrupts the NCL-EGFR complex, and suppresses EGFR-PI3K-AKT signaling, leading to apoptosis and tumor growth inhibition. These findings establish NCL as a promising therapeutic target and highlight hirsutellone-type alkaloids as a novel class of NCL modulators for TNBC treatment.