Discovery of a Novel Selective and Cell-Active N 6 -Methyladenosine RNA Demethylase ALKBH5 Inhibitor

作者：Xianyuan Yang, K. X. Huang, Xu-Nian Wu, Chen Zhang, Yixuan Sun, Yanfeng Gao, Jiawang Zhou, Lijun Tao, Haisheng Zhang, Yinuo Wu, Hai‐Bin Luo, Hongsheng Wang · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.4c01542 · 被引用次数：19 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Cancer-related molecular mechanisms research

N 6 -methyladenosine (m 6 A), the most abundant methylation on mRNA, plays pivotal roles in regulating mRNA biological functions, which affect cell functions. ALKBH5, an m 6 A demethylase, was found to be an oncogene in several cancer types, including triple-negative breast cancer (TNBC). Here, we report a novel and selective ALKBH5 covalent inhibitor, W23 - 1006, through virtual screening and structure optimization. It covalently bonds to the ALKBH5 C200 residue with an IC 50 value of 3.848 μM, representing roughly 30- and 8-fold stronger inhibitory activity than that against FTO and ALKBH3, respectively. Cellular experiments demonstrated that W23-1006 could efficiently enhance the m 6 A level on fibronectin 1 (FN1) mRNA, leading to strong suppression of TNBC cell proliferation and migration in vitro as well as tumor growth and metastasis in vivo. Collectively, our study developed a novel, selective, and cell-active ALKBH5 covalent inhibitor, W23-1006, which could be a potential therapeutic option for cancer, such as TNBC treatment.