9MRE

From DNA-Encoded Library Screening to AM-9747 - an MTA-Cooperative PRMT5 Inhibitor with Potent Oral in vivo Efficacy

This is a non-PDB format compatible entry.

Summary for 9MRE

• Entry DOI: 10.2210/pdb9mre/pdb
• Descriptor: Protein arginine N-methyltransferase 5, Methylosome protein 50, 2-amino-3-methyl-N-[(1R)-1-(pyrimidin-2-yl)ethyl]-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}quinoline-6-carboxamide, ... (8 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: 112941.60

Authors

GhimireRijal, S.,Mukund, S. (deposition date: 2025-01-07, release date: 2025-03-26, Last modification date: 2025-04-02)

Primary citation

Sarvary, I.,Vestergaard, M.,Moretti, L.,Andersson, J.,Peiro Cadahia, J.,Cowland, S.,Flagstad, T.,Franch, T.,Gouliaev, A.,Husemoen, G.,Jacso, T.,Kronborg, T.,Kuropatnicka, A.,Nadali, A.,Madsen, M.,Nielsen, S.R.,Pii, D.,Ryborg, S.R.,Soede, C.,Allen, J.R.,Bourbeau, M.,Li, K.,Liu, Q.,Lo, M.C.,Madoux, F.,Mardirossian, N.,Moriguchi, J.,Ngo, R.,Peng, C.C.,Pettus, L.,Tamayo, N.,Wang, P.,Kapoor, R.,Belmontes, B.,Caenepeel, S.,Hughes, P.,Liu, S.,Slemmons, K.K.,Yang, Y.,Xie, F.,Ghimire-Rijal, S.,Mukund, S.,Glad, S.
From DNA-Encoded Library Screening to AM-9747 : An MTA-Cooperative PRMT5 Inhibitor with Potent Oral In Vivo Efficacy.
J.Med.Chem., 68:6534-6557, 2025

PubMed Abstract: Inhibition of the methyltransferase enzyme PRMT5 by MTA accumulation is a vulnerability of MTAP-deleted cancers. Herein, we report the discovery and optimization of a quinolin-2-amine DEL hit that cooperatively binds PRMT5:MEP50 and MTA to generate a catalytically inhibited ternary complex. X-ray crystallography confirms quinolin-2-amine binding of PRMT5 glutamate-444, while simultaneously exhibiting a hydrophobic interaction with MTA. Lead optimization produced , which selectively inhibits PRMT5-directed symmetric dimethylation of arginine residues of proteins, leading to a potent reduction of cell viability in MTAP-del cells compared to MTAP-WT cells. Once-daily oral dosing of in mouse xenografts is well tolerated, displaying a robust and dose-dependent inhibition of symmetric dimethylation of arginine in MTAP-del tumor-xenografts and significant concomitant tumor growth inhibition without any significant effect on MTAP-WT tumor xenografts.

PubMed: 40102181
DOI: 10.1021/acs.jmedchem.4c03101

Experimental method

X-RAY DIFFRACTION (2.25 Å)