MTA-cooperative PRMT5 inhibitors from cofactor-directed DNA-encoded library screens.

ABSTRACT: Methylthioadenosine phosphorylase (MTAP) gene deletions are frequent in human cancers. Loss of MTAP leads to significantly increased cellular levels of methylthioadenosine (MTA), a cellular metabolite and specific inhibitor of the cell-essential enzyme Protein Arginine Methyltransferase-5 (PRMT5). Using a cofactor-directed screening strategy and DNA-encoded libraries, we identify a class of PRMT5 inhibitors that cooperatively inhibit PRMT5 in the presence of MTA. An optimized inhibitor, AM-9934, selectively inhibits PRMT5 in MTAP-deleted cells and in transplanted tumors while sparing MTAP-expressing counterparts, leading to specific suppression of viability in MTAP-deleted cells. Structural studies show that AM-9934 occupies the arginine substrate pocket

SUBMITTER: Andersson J 

PROVIDER: S-EPMC12107103 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature