Li Gengwu, Chen Wei, Liu Dan, Tang Shibing
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; State Key Laboratory of Respiratory Disease, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Eur J Med Chem. 2025 Jun 5;290:117560. doi: 10.1016/j.ejmech.2025.117560. Epub 2025 Mar 22.
N-methyladenosine (m6A), the most abundant RNA modification in eukaryotic cells, exerts a critical influence on RNA function and gene expression. It has attracted considerable attention within the rapidly evolving field of epitranscriptomics. METTL3 is a key enzyme for m6A modification and is essential for maintaining normal m6A levels. High expression of METTL3 is closely associated with various cancers, including gastric cancer, liver cancer, and leukemia. Inhibiting METTL3 has shown potential in slowing cancer progression, thereby driving the development of METTL3 inhibitors. In this work, we summarize recent advancements in the development of METTL3 inhibitor, with a focus on medicinal chemistry strategies employed during discovery and optimization phases. We explore the application of structure-activity relationship (SAR) studies and protein-targeted degradation techniques, while addressing key challenges associated with their characterization and clinical translation. This review underscores the therapeutic potential of METTL3 inhibitors in modulating epitranscriptomic pathways and aims to offer perspectives for future research in this rapidly evolving field.
N6-甲基腺苷（m6A）是真核细胞中最丰富的RNA修饰，对RNA功能和基因表达具有关键影响。它在快速发展的表观转录组学领域引起了相当大的关注。METTL3是m6A修饰的关键酶，对维持正常的m6A水平至关重要。METTL3的高表达与包括胃癌、肝癌和白血病在内的多种癌症密切相关。抑制METTL3已显示出减缓癌症进展的潜力，从而推动了METTL3抑制剂的开发。在这项工作中，我们总结了METTL3抑制剂开发的最新进展，重点关注发现和优化阶段所采用的药物化学策略。我们探讨了构效关系（SAR）研究和蛋白质靶向降解技术的应用，同时解决了与其表征和临床转化相关的关键挑战。本综述强调了METTL3抑制剂在调节表观转录组途径方面的治疗潜力，并旨在为这个快速发展领域的未来研究提供视角。
