Methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3) (METTL3)

Methyltransferase like 3 (METTL3) is the primary catalytic subunit of the N6-methyladenosine (m6A) methyltransferase complex, acting as the central "writer" of the most abundant internal modification in eukaryotic mRNA [1, 11, 18]. By transferring a methyl group from S-adenosylmethionine (SAM) to adenosine residues, METTL3 regulates critical post-transcriptional processes, including RNA splicing, stability, export, and translation efficiency [3, 10, 18]. In the context of human disease, METTL3 is frequently overexpressed in various malignancies such as acute myeloid leukemia (AML) and several solid tumors, where it promotes oncogenesis by maintaining cancer stemness and facilitating immune evasion [2, 5, 14]. Therapeutic targeting of METTL3 has emerged as a promising strategy, with small-molecule inhibitors designed to competitively bind the SAM active site to reduce global m6A levels and trigger anti-tumor immune responses [8, 10, 16]. Beyond oncology, METTL3 is implicated in inflammatory disorders, neurodegenerative diseases, and viral replication, highlighting its significance as a versatile regulator of the epitranscriptomic landscape [3, 13, 21].

Other names

N6-adenosine-methyltransferase catalytic subunitMT-A70Methyltransferase-like protein 3MTCCPIME4Spo8Inducer of meiosis 4 homolog

Drugs targeting METTL3 primarily function as competitive inhibitors of the S-adenosylmethionine (SAM) binding site within the enzyme's catalytic domain [8, 10]. This inhibition prevents the transfer of methyl groups to the N6 position of adenosine in target mRNA, leading to a global reduction in m6A levels [3, 14, 16]. The resulting decrease in m6A modification destabilizes oncogenic transcripts and alters translation, suppressing tumor cell proliferation and stemness [1, 2, 7]. Additionally, METTL3 inhibition has been shown to activate innate immune signaling pathways, such as the interferon response, which enhances the recruitment and activation of anti-tumor immune cells like M1 macrophages and T-cells [14, 15, 16].