MAT2A

Class

Allosteric MAT2A inhibitor (small molecule)

Pathway

MTAP-deletion synthetic lethality (SAM/PRMT5-dependent splicing and DNA repair)

MAT2A (methionine adenosyltransferase 2A) is the principal enzyme that synthesizes S-adenosylmethionine (SAM), the cell's universal methyl donor, from methionine and ATP. SAM fuels methylation reactions throughout the cell, including those carried out by PRMT5, an enzyme that methylates arginine residues on proteins involved in RNA splicing and DNA repair. Inhibiting MAT2A is being pursued as a targeted strategy in cancers that carry deletion of the MTAP gene, a genetic lesion frequently found alongside loss of the tumor-suppressor locus CDKN2A in several solid tumor types. MTAP normally clears a metabolic byproduct called methylthioadenosine (MTA); when MTAP is deleted, MTA accumulates and partially blocks PRMT5 by competing with SAM. This leaves MTAP-deleted tumor cells operating with reduced PRMT5 activity and heightened dependence on the SAM that remains. Blocking MAT2A further lowers SAM levels, disproportionately compromising PRMT5 function in these already-vulnerable cells while sparing normal, MTAP-intact tissue that can clear MTA and buffer the loss. This selective vulnerability is an example of synthetic lethality, where a genetic deletion creates dependence on a second pathway that can be therapeutically exploited. The approach is being explored across MTAP-deleted cancers, including central nervous system, lung, pancreatic, and mesothelial tumors.