Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability
Silong Zhang, Luolong Qing, Ziwei Wang, Yu Zhang, Yuanyuan Li, Huaxiang Fang, Yi Liu, Huan He
Abstract
Inhibition of methionine adenosyltransferase 2A (MAT2A) in cancers with a deletion of methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality, thus receiving significant interest in the field of precise cancer treatment. Herein, we report the discovery of a tetrahydrobenzo[4,5]imidazo[1,2- a ]pyrazine fragment which occupies the MAT2A allosteric pocket. The lead compound 8 exhibited extremely high potency to inhibit MAT2A enzymatic activity (IC 50 = 18 nM) and proliferation of MTAP-null cancer cells (IC 50 = 52 nM). 8 had a favorable pharmacokinetic profile with a bioavailability of 116% in mice. More importantly, introducing an amide motif ( 28 ) to the core structure raised the plasma drug exposure from 11 718 to 41 192 ng·h·mL –1 . 28 displayed a significantly better in vivo potency than AG-270, which is being evaluated in clinical trails, and induced −52% tumor regression in a xenograft MTAP-depleted colon tumor model.