SCR‐7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the <i>S</i>‐adenosylmethionine‐competitive or the methylthioadenosine‐cooperative protein arginine methyltransferase 5 inhibitors in meth

The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was found to elicit synthetic lethality in methylthioadenosine phosphorylase (<i>MTAP</i>)-deleted cancers, which occur in about 15% of all cancers. Here, we described a novel MAT2A inhibitor, SCR-7952 with potent and selective antitumor effects on <i>MTAP</i>-deleted cancers in both in vitro and in vivo. The cryo-EM data indicated the high binding affinity and the allosteric binding site of SCR-7952 on MAT2A. Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. A systematic evaluation of combination between SCR-7952 and different types of protein arginine methyltransferase 5 (PRMT5) inhibitors indicated remarkable synergistic interactions between SCR-7952 and the <i>S</i>-adenosylmethionine-competitive or the methylthioadenosine-cooperative PRMT5 inhibitors, but not substrate-competitive ones. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of <i>MTAP</i>-deleted cancers, both monotherapy and in combination with PRMT5 inhibitors.