N⁶-methyladenosine (m⁶A) is an abundant internal RNA modification^1,2 that is catalysed predominantly by the METTL3–METTL14 methyltransferase complex^3,4. The m⁶A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown^5,6,7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3–METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m⁶A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy.

N ⁶ -甲基腺苷 (m ⁶ A) 是一种丰富的内部 RNA 修饰^1,2，主要由 METTL3–METTL14 甲基转移酶复合物^3,4催化。m ⁶ A 甲基转移酶 METTL3 与急性髓性白血病 (AML) 的发生和维持有关，但针对这种酶的治疗应用潜力仍然未知^5,6,7. 在这里，我们介绍了 STM2457（一种高效和选择性的一流 METTL3 催化抑制剂）的鉴定和表征，以及与 METTL3–METTL14 复合的 STM2457 的晶体结构。用 STM2457 治疗肿瘤会导致 AML 生长减少以及分化和细胞凋亡增加。这些细胞效应伴随着 m ^{6的选择性减少}已知致白血病 mRNA 的 A 水平及其表达的降低与翻译缺陷一致。我们证明，体内 METTL3 的药理学抑制导致各种 AML 小鼠模型的植入受损和存活时间延长，特别针对 AML 的关键干细胞亚群。总的来说，这些结果揭示了 METTL3 的抑制作为一种潜在的 AML 治疗策略，并提供了概念证明，即靶向 RNA 修饰酶代表了一种有希望的抗癌治疗途径。