Target Ligand Separation and Identification of Isoforsythiaside as a Histone Lysine-Specific Demethylase 1 Covalent Inhibitor Against Breast Cancer Metastasis

文献类型： 外文期刊

第一作者： Gu, Mengzhen

作者： Gu, Mengzhen;Xu, Xiaoqing;Wang, Xiaoping;Wang, Yun;Zhao, Yu;Hu, Xiaoxian;Han, Chao;Zhu, Lu;Deng, Zhenzhong

作者机构：

期刊名称：JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：6.8； 五年影响因子：7.2 ）

ISSN： 0022-2623

年卷期： 2024 年 67 卷 21 期

页码：

收录情况： SCI

摘要： Histone lysine-specific demethylase 1 (LSD1) is hyperactive in breast cancer, which is associated with the metastasis of the tumor. Current irreversible LSD1 inhibitors are all synthesized by covalently binding to the flavin adenine dinucleotide cofactor, which often have side effects due to the high affinity for a variety of targets. Here, we identified isoforsythiaside (IFA), a natural phenylpropanoid glycoside isolated from Forsythia suspensa, as a novel covalent inhibitor of LSD1. The target ligand fishing technique and LC-MS/MS analysis identified that IFA could covalently bind to the Ser817 residue of LSD1 by alpha,beta-unsaturated ketone moiety to block the amine oxidase-like domain of LSD1. Moreover, RBMS3/Twist1/MMP2, the downstream signaling pathway of LSD1, was activated after IFA treatment to inhibit the metastasis of MDA-MB-231 cells in vitro and in vivo. This study provided novel molecular templates for development of LSD1 covalence-binding inhibitor and laid a foundation for developing agents against breast carcinoma metastasis for targeting LSD1.

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