m1A and m6A RNA Methylations as Druggable Targets in Cancer

Epitranscriptomic modifications, particularly RNA methylations, have emerged as regulators of gene expression, with their dysregulation acting as a key factor in tumorigenesis and metastatic progression. This review evaluates the therapeutic landscapes of N6-methyladenosine (m6A) and N1-methyladenosine (m1A) modifications in cancer. While the m6A machinery predominantly dictates mRNA turnover and stability, the m1A network is uniquely positioned to drive translational reprogramming, allowing malignant cells to endure severe microenvironmental stress and evade cell death. Despite positional and chemical differences, these modifications exhibit profound epitranscriptomic crosstalk through shared regulatory proteins. Here, we comprehensively analyze current pharmacological strategies targeting the m6A axis, highlighting the transition from classical small-molecule inhibitors of regulatory proteins of these methylations, such as methyltransferase-like 3 (METTL3), fat mass and obesity-associated protein (FTO), and AlkB homolog 5 (ALKBH5), to the novel event-driven approach of proteolysis-targeting chimeras (PROTACs). Furthermore, we assess the emerging therapeutic potential of the m1A regulatory machinery, positioning tRNA methyltransferase 6/61A (TRMT6/61A) writers and AlkB homolog 1 to 3 (ALKBH1-3) erasers as promising therapeutic targets. Finally, we discuss clinical successes and current translational obstacles, including off-target toxicity, pharmacokinetic limitations, and epitranscriptomic escape, emphasizing that site-specific modulation and smart precision therapies will dictate the future of oncology.