Recent advances in medicinal chemistry strategies for the development of METTL3 inhibitors.

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.