AGI-24512 is a highly potent, cell-active methionine adenosyltransferase 2α (MAT2A) inhibitor with enzymatic IC50 of 8 nM. AGI-24512 reduces cellular S-adenosylmethionine levels, S-adenosylmethionine de novo biosynthesis, and symmetric dimethyl arginine levels. AGI-24512 selectively reduces growth of MTAP−/− cancer cells, with limited effects on MTAP WT lines. AGI-24512 induces MTAP−/− genotype-selective cell-cycle delays and DNA damage. AGI-24512 affected multiple alternative splicing events in MTAP−/− but not in WT cells, affects PRMT5 downstream splicing biology.
