9NWY

Discovery of MTA-cooperative PRMT5 Inhibitors from Co-factor directed DNA-Encoded Library Screens

This is a non-PDB format compatible entry.

Summary for 9NWY

• Entry DOI: 10.2210/pdb9nwy/pdb
• Related: 9MRE
• Descriptor: Protein arginine N-methyltransferase 5, Methylosome protein 50, 2-amino-3-methyl-N-(2-methylpropyl)-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}quinoline-6-carboxamide, ... (5 entities in total)
• Functional Keywords: prmt5, mta-cooperative inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 111878.35

Authors

GhimireRijal, S.,Mukund, S. (deposition date: 2025-03-24, release date: 2025-05-07, Last modification date: 2025-11-19)

Primary citation

Andersson, J.,Cowland, S.,Vestergaard, M.,Yang, Y.,Liu, S.,Fang, X.,Mukund, S.,Ghimire-Rijal, S.,Carter, C.,Chung, G.,Jacso, T.,Sarvary, I.,Hughes, P.E.,Gouliaev, A.,Payton, M.,Belmontes, B.,Caenepeel, S.,Franch, T.,Glad, S.,Husemoen, B.,Nielsen, S.J.
MTA-cooperative PRMT5 inhibitors from cofactor-directed DNA-encoded library screens.
Proc.Natl.Acad.Sci.USA, 122:e2425052122-e2425052122, 2025

PubMed Abstract: Methylthioadenosine phosphorylase () gene deletions are frequent in human cancers. Loss of 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 -deleted cells and in transplanted tumors while sparing -expressing counterparts, leading to specific suppression of viability in -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 -deleted cancers.

PubMed: 40377999
DOI: 10.1073/pnas.2425052122

Experimental method

X-RAY DIFFRACTION (3.1 Å)