Dutheuil Guillaume, Oukoloff Killian, Korac Julien, Lenoir François, El Bousmaqui Mohamed, Probst Nicolas, Lapin Alexey, Nakhabina Galina, Sorlet Catherine, Parmentier Nicolas, Karila Delphine, Ghavtadze Nugzar, Casault Paméla, Claridge Stephen, Sapmaz Selma, Slater Martin J, Fraser Graeme L
Epics Therapeutics SA, rue Adrienne Bolland 47, Gosselies 6041, Belgium.
Paraza Pharma, Inc., 2525 Avenue Marie Curie, Montréal H4S 2E1, Canada.
J Med Chem. 2025 Feb 13;68(3):2981-3003. doi: 10.1021/acs.jmedchem.4c02225. Epub 2025 Jan 30.
METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-methyladenosine (mA), the most abundant modification to mRNA. The prevalence of mA and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML), thereby making METTL3 an attractive target for cancer therapeutics. We report herein the discovery and optimization of small-molecule inhibitors of METTL3, culminating in the selection of as an proof-of-concept compound. potently inhibits the enzymatic activity of METTL3, has favorable PK parameters, and demonstrates efficacy in preclinical oncology models, indicating that pharmacological inhibition of METTL3 is a viable strategy for the treatment of liquid and solid tumors.
METTL3是一种RNA甲基转移酶，主要负责在mRNA上添加N-甲基腺苷（m⁶A），这是mRNA中最丰富的修饰。m⁶A的普遍性以及METTL3的活性和表达与急性髓系白血病（AML）的发生和进展有关，因此使METTL3成为癌症治疗的一个有吸引力的靶点。我们在此报告了METTL3小分子抑制剂的发现和优化，最终选择了作为概念验证化合物。 能有效抑制METTL3的酶活性，具有良好的药代动力学参数，并在临床前肿瘤模型中显示出疗效，表明对METTL3进行药理抑制是治疗液体和实体瘤的一种可行策略。
