A RationallyEngineered MAGL-Activatable FluorogenicProbe Enables Efficient Discovery of Anti-Inflammatory and HepatoprotectiveAgents

作者：Lele Liu, Shimin Hou, Le Chen, Kangdi Yang, Guanghao Zhu, Jiaqian Miao, Xiaoya Qin, Weiyu Wang, 易豪精, Haitao Zhang, Xiaodi Yang, Yufan Fan, Qigui Lu, Zhaobin Guo, Hui Tang, Guangbo Ge · 发表于：Journal of Medicinal Chemistry · 年份：2026 · DOI：10.1021/acs.jmedchem.6c01300 · 研究领域：Cannabis and Cannabinoid Research、Molecular Sensors and Ion Detection、Pharmacological Receptor Mechanisms and Effects

Abstract Targeted inhibition of monoacylglycerol lipase (MAGL) represents a promising therapeutic strategy for inflammatory diseases and drug-induced hepatotoxicity. However, the lack of robust screening assays hindered the efficient discovery of potent MAGL inhibitors. Herein, a high-performance MAGL-activatable fluorogenic probe, CN-2, was developed through three-round structural optimization of luminescent scaffold, N-site substituent, and recognition moiety. CN-2 displayed an optimal combination of signal enhancement, detection sensitivity, and favorable kinetic behaviors. CN-2-based high-throughput screening platform efficiently identified three potent competitive MAGL inhibitors (A5, A11, and F10). These inhibitors potently inhibited intracellular MAGL activity in macrophages, significantly elevated endogenous 2-AG levels, and attenuated LPS-induced inflammatory responses. Furthermore, these agents conferred significant hepatoprotective effects against acetaminophen (APAP)-induced injury in both hepatocytes and human liver organoids by reducing ALT, AST, LDH, and ROS, and restoring mitochondrial membrane potential. Collectively, this work establishes a practical and efficient platform for discovering MAGL inhibitors as novel anti-inflammatory and hepatoprotective agents.