Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy

Synthetic
lethality has recently emerged as a new approach for
the treatment of mutated genes that were previously considered undruggable.
Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with
deletion of the methylthioadenosine phosphorylase (MTAP) gene leads
to synthetic lethality and thus has attracted significant interest
in the field of precise anticancer drug development. Herein, we report
the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug
design. Further optimization led to compound 39, which
has a high potency for inhibiting MAT2A and a remarkable selectivity
for MTAP-deleted cancer cell lines. Compound 39 has a
favorable pharmacokinetic profile with high plasma exposure and oral
bioavailability, and it exhibits significant efficacy in xenograft
MTAP-depleted models. Moreover, 39 demonstrates excellent
brain exposure with a Kpuu of 0.64 in
rats.