The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. The study was conducted to report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. MAT2Ai reduce PRMT5 activity affecting mRNA splicing and inducing DNA damage. The methylthioadenosine phosphorylase ( MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A ( CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP −/− cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes. As a conclusion it is observed that using RNA sequencing and proteomics, researchers demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. AGI-24152 and AG-270 reduce proliferation of cancer cells and tumors that lack MTAP. Antiproliferative effects of AG-270 are synergistic with taxanes in vitro and in vivo.