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 the field of medicinal chemistry due to its
implication as a synthetic lethal target in cancers with the deletion
of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report
the identification of novel MAT2A inhibitors with distinct in vivo properties that may enhance their utility in treating
patients. Following a high-throughput screening, we successfully applied
the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270, to rapidly redesign 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
MAT2A inhibitors will create new opportunities to explore the potential
therapeutic effects of SAM modulation in the central nervous system
(CNS).