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MTA-cooperative PRMT5 inhibitors from cofactor-directed DNA-encoded library screens
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DOI：10.1073/pnas.2425052122.png)
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Abstract
En 中文
Methylthioadenosine phosphorylase (MTAP) gene deletions are frequent in human cancers. Loss ofMTAP 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 of MTA-bound PRMT5. This study introduces a broadly applicable method for directed DNA-encoded library screening toward a desired mechanistic outcome and highlights MTA-selective PRMT5 inhibition as an attractive therapeutic strategy with a potentially broad therapeutic index in patients with MTAP-deleted cancers.
Keywords:
DNA-encoded library screens
PRMT5
cancer
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IF:
9.1
Papers:
10.8W
Citations:
73.5W
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