8VEW

Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 24

これはPDB形式変換不可エントリーです。

8VEW の概要

• エントリーDOI: 10.2210/pdb8vew/pdb
• 分子名称: Protein arginine N-methyltransferase 5, Methylosome protein 50, 5'-DEOXY-5'-METHYLTHIOADENOSINE, ... (7 entities in total)
• 機能のキーワード: mtap-null, sam, mta, inhibitor, mta-cooperative, transferase, transferase-inhibitor complex, 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: 112452.78

構造登録者

Whittington, D.A. (登録日: 2023-12-20, 公開日: 2024-04-24, 最終更新日: 2024-10-16)

主引用文献

Cottrell, K.M.,Briggs, K.J.,Whittington, D.A.,Jahic, H.,Ali, J.A.,Davis, C.B.,Gong, S.,Gotur, D.,Gu, L.,McCarren, P.,Tonini, M.R.,Tsai, A.,Wilker, E.W.,Yuan, H.,Zhang, M.,Zhang, W.,Huang, A.,Maxwell, J.P.
Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP -Deleted Cancers.
J.Med.Chem., 67:6064-6080, 2024

PubMed Abstract: It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the gene if the inhibitors can leverage the consequence of deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of -deleted (MTAP-null) cells compared to intact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with loss.

PubMed: 38595098
DOI: 10.1021/acs.jmedchem.4c00133

実験手法

X-RAY DIFFRACTION (2.69 Å)