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MTA-cooperative PRMT5 inhibitors from cofactor-directed DNA-encoded library screens
Jan Andersson1, Sanne Cowland1, Mikkel Vestergaard1
1Amgen Research, Copenhagen DK-2100, Denmark.
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 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.
Insights
Methylthioadenosine phosphorylase (MTAP) gene deletions increase a metabolite that inhibits PRMT5. Researchers developed a novel inhibitor, AM-9934, that selectively targets this enzyme in MTAP-deleted cancer cells, offering a new therapeutic strategy.
Area of Science:
- Biochemistry
- Oncology
- Drug Discovery
Background:
- Methylthioadenosine phosphorylase (MTAP) gene deletions are common in human cancers.
- MTAP loss elevates methylthioadenosine (MTA), an inhibitor of Protein Arginine Methyltransferase-5 (PRMT5).
Purpose of the Study:
- To identify PRMT5 inhibitors that function in the presence of MTA.
- To develop a targeted therapy for MTAP-deleted cancers.
Main Methods:
- Cofactor-directed screening and DNA-encoded libraries were employed.
- Structural studies elucidated the binding mechanism of the inhibitor.
Main Results:
- A novel class of PRMT5 inhibitors was identified, cooperative in the presence of MTA.
- Optimized inhibitor AM-9934 selectively targets PRMT5 in MTAP-deleted cells and tumors.
- AM-9934 suppresses viability specifically in MTAP-deleted cancer cells.
Conclusions:
- MTA-selective PRMT5 inhibition is a promising therapeutic strategy for MTAP-deleted cancers.
- The developed screening method is broadly applicable for targeted drug discovery.
