Furo[2,3-f]quinazolin-7(6H)-one Derivatives as Potent, Selective, and Orally Bioavailable MAT2A Inhibitors for...

Methionine adenosyltransferase 2A (MAT2A) has emerged as a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deleted cancers, which account for approximately 15% of human tumors and currently lack effective therapies. However, existing MAT2A inhibitors often suffer from limited potency, suboptimal selectivity, and undesirable toxicity. Herein, we report a series of tricyclic furo[2,3-f]quinazolin-7(6H)-one derivatives as MAT2A inhibitors based on structure-based drug design. Among them, compound 18 (ZS34) exhibited potent MAT2A inhibitory activity (IC₅₀ = 13.7 nM) and selectively suppressed the growth of MTAP-deficient cancer cells. Furthermore, 18 demonstrated on-target engagement in MTAP-deficient cells, as evidenced by inhibition of SAM synthesis, reduction of SDMA levels, and induction of DNA damage. Additionally, 18 displayed minimal hERG and UGT1A1 liabilities along with favorable oral pharmacokinetics. In the HCT116 MTAP^-/- xenograft mouse model, the oral administration of 18 demonstrated significant antitumor efficacy without obvious toxicity. These results support 18 as a promising candidate for targeting MTAP-deficient cancers.