Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads

Inhibition of the S-adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A(MAT2A), has received significant interest in thefield of medicinal chemistry due to its implication as a synthetic lethal target incancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novelMAT2A inhibitors with distinctin vivoproperties that may enhance their utility in treating patients. Following a high-throughputscreening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor,AG-270, to rapidlyredesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound,AGI-41998, and a potent, but limited brain-penetrant compound,AGI-43192. We hope that the identification and first disclosure of brain-penetrant MAT2Ainhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system(CNS).