Key epitranscriptomic players have been increasingly characterized for their structural features and their involvement in several diseases. Accordingly, the design and synthesis of novel epitranscriptomic modulators have started opening a glimmer for drug discovery. m6A is a reversible modification occurring on a specific site and is catalyzed by three sets of proteins responsible for opposite functions. Writers (e.g., methyl-transferase-like protein (METTL) 3/METTL14 complex and METTL16) introduce the methyl group on adenosine N-6, by transferring the methyl group from the methyl donor S-adenosylmethionine (SAM) to the substrate. Despite the rapidly advancing drug discovery progress on METTL3/METTL14, the METTL16 m6A writer has been marginally explored so far. We herein provide the first comprehensive overview of structural and biological features of METTL16, highlighting the state of the art in the field of its biological and structural characterization. We also showcase initial efforts in the identification of structural templates and preliminary structure−activity relationships for METTL16 modulators.
■ SIGNIFICANCE• The term "epitranscriptomics" refers to the post-transcriptional modifications to RNA.• One of the key RNA modifications is the introduction of a methyl on adenosine N-6 (m6A), catalyzed by METTL3/ METTL14 and METTL16.• METTL16 is involved in several diseases; only recently structural studies emerged, providing insights about METTL16 substrates and preliminary hints about its druggability.• This Perspective focuses on the latest advancements in targeting METTL16, discussing design strategies and challenges for the development of METTL16 inhibitors.