Identification of a Sonically Activated Degrader of Methionine Adenosyltransferase 2A by an Approach Assisted with the Hole-Electron Analysis.

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 as a sonically activated degrader of MAT2A. Upon sonication, can generate reactive oxygen species to specifically degrade cellular MAT2A via rapid oxidative reactions.

Exploring the structural-activity relationship of hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine derivatives as potent and orally-bioavailable PARP7 inhibitors.

PARP7 has emerged as a promising anti-tumor target due to its crucial roles in nucleic acid sensing and immune regulation. Herein, we explored the structural-activity relationship of tricyclic PARP7 inhibitors containing a hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine motif. The effects of the chirality of the fused rings, the group conjugated to the fused rings, and the size of the linker on PARP7 inhibition were fully investigated.