Discovery, Optimization, and Preclinical Pharmacology of EP652, a METTL3 Inhibitor with Efficacy in Liquid and Solid Tumor Models

• Published in: Journal of medicinal chemistry Vol. 68; no. 3; pp. 2981 - 3003
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.02.2025; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Chemistry, Medicinal; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Humans; Life Sciences & Biomedicine; Methyltransferases - antagonists & inhibitors; Methyltransferases - metabolism; Mice; Neoplasms - drug therapy; Neoplasms - pathology; Pharmacology & Pharmacy; Rats; Science & Technology; Structure-Activity Relationship; Xenograft Model Antitumor Assays; RNA; LEUKEMIA
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c02225

METTL3 is the RNA methyltransferase predominantly responsible for the addition of N6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A 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 EP652 as an in vivo proof-of-concept compound. EP652 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.