9PY0

PRMT5 Bound to Compound 12 and MTA

これはPDB形式変換不可エントリーです。

9PY0 の概要

• エントリーDOI: 10.2210/pdb9py0/pdb
• 分子名称: Protein arginine N-methyltransferase 5, Methylosome protein 50, 4-amino-N'-(cyclopropanecarbonyl)-N',1-dimethyl-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-pyrazolo[4,3-c]quinoline-8-carbohydrazide, ... (5 entities in total)
• 機能のキーワード: methyltransferase, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 112420.84

構造登録者

Ferrao, R. (登録日: 2025-08-06, 公開日: 2026-01-07, 最終更新日: 2026-01-14)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.36 Å)