Small molecules capable of modulating methionine adenosyltransferase
2A (MAT2A) are of significant interest in precise cancer therapeutics.
Herein, we raised the hole–electron Coulombic attraction as
a reliable molecular descriptor for predicting the reactive oxygen
generation capacity of MAT2A inhibitors, based on which we discovered
compound H3 as a sonically activated degrader of MAT2A.
Upon sonication, H3 can generate reactive oxygen species
to specifically degrade cellular MAT2A via rapid oxidative reactions.
Combination of H3 and sonication induced 87% MAT2A depletion
in human colon cancer cells, thus elevating its antiproliferation
effects by 8-folds. In vivo, H3 had
a favorable pharmacokinetic profile (bioavailability = 77%) and ADME
properties. Owing to the MAT2A degradation merits, H3 at a dosage of 10 mg/kg induced 31% tumor regression in xenograft
colon tumor models. The significantly boosted antitumor potency can
potentially alleviate the toxicity of high-dose MAT2A inhibitors to
normal cells and tissues, especially to the liver.