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

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 <b>EP652</b> as an <i>in vivo</i> proof-of-concept compound. <b>EP652</b> 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.