METTL3 from Target Validation to the First Small-Molecule Inhibitors: A Medicinal Chemistry Journey

[Image: see text] RNA methylation is a critical mechanism for regulating the transcription and translation of specific sequences or for eliminating unnecessary sequences during RNA maturation. METTL3, an RNA methyltransferase that catalyzes the transfer of a methyl group to the N(6)-adenosine of RNA, is one of the key mediators of this process. METTL3 dysregulation may result in the emergence of a variety of diseases ranging from cancer to cardiovascular and neurological disorders beyond contributing to viral infections. Hence, the discovery of METTL3 inhibitors may assist in furthering the understanding of the biological roles of this enzyme, in addition to contributing to the development of novel therapeutics. Through this work, we will examine the existing correlations between METTL3 and diseases. We will also analyze the development, mode of action, pharmacology, and structure–activity relationships of the currently known METTL3 inhibitors. They include both nucleoside and non-nucleoside compounds, with the latter comprising both competitive and allosteric inhibitors.