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(1