化学
脱甲基酶
配体(生物化学)
赖氨酸
癌症
组蛋白
乳腺癌
溴尿嘧啶
生物化学
共价键
转移
癌症研究
受体
内科学
氨基酸
有机化学
生物
DNA
医学
作者
Mengzhen Gu,Xiaoqing Xu,Xiaoping Wang,Li Wang,Yong‐Min Liang,Xiaoxian Hu,Lu Zhu,Zhenzhong Deng,Chao Han
标识
DOI:10.1021/acs.jmedchem.4c02277
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 α,β-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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