Recent advances in small molecules targeting the METTL3.

N⁶-methyladenosine (m⁶A) is the most prevalent internal modification of eukaryotic mRNA, playing a crucial role in the regulation of gene expression. Methyltransferase-like 3 (METTL3), a key catalytic component of the m⁶A methyltransferase complex, is primarily responsible for the deposition of m⁶A on target RNA. Recent studies have revealed that METTL3 contributes to diverse pathological processes, particularly tumorigenesis, through both m⁶A-dependent and independent mechanisms. As a result, METTL3 has attracted increasing interest as a potential therapeutic target across various cancer types. This review summarizes recent advances in the discovery of small molecules targeting METTL3, including substrate-competitive inhibitors, allosteric inhibitors, and proteolysis-targeting chimeras (PROTACs). It also discusses the strategies in their discovery, the associated structural features, and the remaining challenges and future directions in this field. Overall, these efforts provide valuable insights into the design and discovery of METTL3-targeted therapeutics with potential clinical applications.