Discovery of a Potent, Selective, and Orally Bioavailable Achiral MAT2A Inhibitor for Treating MTAP-Deficient Cancers.

Targeting methionine adenosyltransferase 2A (MAT2A) represents an attractive synthetic lethal approach for treating methylthioadenosine phosphorylase (MTAP)-deleted cancers. Despite promising progress in the development of MAT2A inhibitors, many reported compounds remain limited by insufficient selectivity, systemic toxicity, and the stereochemical complexities of atropisomerism. Through structure-guided optimization of our previously reported atropisomeric lead, we identified ZS97 (26), a potent MAT2A inhibitor that lacks axial chirality. The nonatropisomeric nature simplifies pharmacological development by avoiding the need for asymmetric synthesis or chiral resolution. ZS97 demonstrated potent enzymatic inhibition, effectively depleting intracellular SAM and suppressing downstream PRMT5-mediated methylation. This biochemical blockade selectively triggered the DNA damage response and cell growth inhibition in MTAP-deficient cancer cells. Furthermore, ZS97 exhibited favorable oral bioavailability and induced significant tumor inhibition in an NCI-H838 xenograft model without associated weight loss. These findings highlight ZS97 as a structurally optimized orally active candidate with therapeutic potential for MTAP-deficient cancers.