9PXZ

PRMT5 Bound to Compound 6 and MTA

This is a non-PDB format compatible entry.

Summary for 9PXZ

• Entry DOI: 10.2210/pdb9pxz/pdb
• Descriptor: Protein arginine N-methyltransferase 5, Methylosome protein 50, 4-amino-1-methyl-N-[(1R)-1-(pyrimidin-2-yl)ethyl]-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-pyrazolo[4,3-c]quinoline-8-carboxamide, ... (5 entities in total)
• Functional Keywords: methyltransferase, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 112429.85

Authors

Ferrao, R. (deposition date: 2025-08-06, release date: 2026-01-07, Last modification date: 2026-01-14)

Primary citation

Debien, L.,Armstrong, M.K.,Farr, J.D.,Ferrao, R.D.,Gupta, P.L.,Niu, C.,Anderson, A.J.,Benner, P.,Bristol, A.N.,Chin, E.,Chou, C.,Deng, Y.,Fu, X.,Gheiratmand, M.,Hull, S.M.,Hung, J.C.,June, B.,Kirschman, J.H.,Le, H.,Malik, B.,Mitchell, M.L.,Mukherjee, P.K.,Nguyen, S.V.,Notte, G.T.,Orf, J.,Roa, D.E.,Santos, R.,Schrier, A.J.,Spence, K.A.,Sura, R.,Yang, Z.Y.,Zane, D.,Zahabian, A.N.,Zavorotinskaya, T.
Discovery of Bis-Acyl Hydrazides as Potent and Bioavailable MTA-Cooperative PRMT5 Inhibitors: A Case Study of Leveraging the Deuterium Kinetic Isotope Effect.
J.Med.Chem., 69:289-304, 2026

PubMed Abstract: We describe the discovery of a series of potent, selective, and orally bioavailable bis-acyl hydrazide inhibitors targeting the PRMT5·MTA complex for the treatment of MTAP-deleted cancers. Key to this discovery was the identification of major metabolite , resulting from -demethylation of lead inhibitor compound , as a potent hERG inhibitor. Leveraging the kinetic isotope effect, we generated methyl- analog which reduced the formation of in vivo, resulting in acceptable safety margins and an improved pharmacokinetic profile. Our data suggest this strategy could be employed more broadly to reduce undesirable metabolism of methylated amines.

PubMed: 41429045
DOI: 10.1021/acs.jmedchem.5c02392

Experimental method

X-RAY DIFFRACTION (2.47 Å)