Structure-Based Discovery of a Series of Novel MAT2a Inhibitors

Methionine adenosyltransferase 2a (MAT2a) has emerged as a promising therapeutic target due to its role in the synthetic lethality mechanism associated with MTAP-deficient tumors. In this study, we describe our efforts to identify a novel series of MAT2a inhibitors through a fragment-based joining strategy, leading to the development of a single molecule that occupies the allosteric site of the MAT2a dimer. Guided by the costructure of AZ-28 in complex with the MAT2a dimer, compound 9 was synthesized, demonstrating potent MAT2a inhibition (IC₅₀ = 20 nM) and significantly enhanced antiproliferative activity (IC₅₀ = 10 nM against HAP1MTAP^-/- cells). Moreover, compound 9 exhibited improved selectivity compared to both AZ-28 and AG-270.