Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability

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 (IC50 = 18 nM) and proliferation of MTAP-null
cancer cells (IC50 = 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.