9G4W

Crystal structure of the human METTL3-METTL14 in complex with small molecule inhibitor Compound 59

これはPDB形式変換不可エントリーです。

9G4W の概要

• エントリーDOI: 10.2210/pdb9g4w/pdb
• 関連するPDBエントリー: 9G4S 9G4U
• 分子名称: N6-adenosine-methyltransferase catalytic subunit, N6-adenosine-methyltransferase non-catalytic subunit, 4-[(3~{R})-3-(cyclopropylmethylamino)piperidin-1-yl]-1-[(1~{R})-1-[4-(6-pyrrolidin-1-ylpyrazin-2-yl)-1,2,3-triazol-1-yl]ethyl]pyridin-2-one, ... (5 entities in total)
• 機能のキーワード: mettl3 mettl14 inhibitor epics, rna binding protein
• 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: 57548.87

構造登録者

Dutheuil, G.,Oukoloff, K. (登録日: 2024-07-16, 公開日: 2025-02-12, 最終更新日: 2025-08-27)

主引用文献

Dutheuil, G.,Oukoloff, K.,Korac, J.,Lenoir, F.,El Bousmaqui, M.,Probst, N.,Lapin, A.,Nakhabina, G.,Sorlet, C.,Parmentier, N.,Karila, D.,Ghavtadze, N.,Casault, P.,Claridge, S.,Sapmaz, S.,Slater, M.J.,Fraser, G.L.
Discovery, Optimization, and Preclinical Pharmacology of EP652, a METTL3 Inhibitor with Efficacy in Liquid and Solid Tumor Models.
J.Med.Chem., 68:2981-3003, 2025

PubMed Abstract: METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-methyladenosine (mA), the most abundant modification to mRNA. The prevalence of mA and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML), thereby making METTL3 an attractive target for cancer therapeutics. We report herein the discovery and optimization of small-molecule inhibitors of METTL3, culminating in the selection of as an proof-of-concept compound. potently inhibits the enzymatic activity of METTL3, has favorable PK parameters, and demonstrates efficacy in preclinical oncology models, indicating that pharmacological inhibition of METTL3 is a viable strategy for the treatment of liquid and solid tumors.

PubMed: 39883878
DOI: 10.1021/acs.jmedchem.4c02225

実験手法

X-RAY DIFFRACTION (1.85 Å)