Journey of Methionine Adenosyltransferase 2A Inhibitors: From Bench to Advanced Clinical Trials

Methionine adenosyltransferase 2A (MAT2A) represents a promising target in precision oncology, especially for cancers with methylthioadenosine phosphorylase (MTAP) deletions. MAT2A inhibition induces synthetic lethality in MTAP-deleted cancers by depleting <i>S</i>-adenosylmethionine (SAM) and enhancing the inherent suppression of protein arginine methyltransferase 5 (PRMT5). Here, we trace the evolution of MAT2A inhibitors from early substrate-competitive molecules to allosteric inhibitors now in clinical evaluation. We discuss the design of next-generation inhibitors with improved potency, selectivity, and pharmacokinetic properties, including central nervous system penetration.