Discovery of 2(1H)‑Quinoxalinone Derivatives as Potent and Selective MAT2A Inhibitors for the Treatment of MTAP-Deficient Cancers

Methionine adenosyltransferase 2A (MAT2A) has emerged as a synthetic lethal drug target in cancers bearing homozygous methylthioadenosine phosphorylase (MTAP) gene deletion. Despite the remarkable progress in the discovery and development of MAT2A inhibitors, current understanding about the selectivity of these compounds toward MTAP-deficient cancers is relatively limited. To improve the selectivity of MAT2A inhibitors for MTAP-deficient cancers remains a significant challenge. We herein reported the discovery of a series of novel MAT2A inhibitors with a 2(1H)-quinoxalinone scaffold through structure-based drug design and systematic SAR exploration. Among them, compound 28 exhibited good inhibitory activity against the enzymatic activity of MAT2A, and the significantly improved selectivity in killing MTAP-deficient cancer cells. Compound 28 also showed favorable pharmacokinetic properties and the improved in vivo anticancer activity in MTAP-deficient tumor models. These findings suggest new directions for the discovery and development of highly selective MAT2A inhibitors.