8XB0

Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with SAM and Compound 292

8XB0 の概要

• エントリーDOI: 10.2210/pdb8xb0/pdb
• 関連するPDBエントリー: 8XAR
• 分子名称: S-adenosylmethionine synthase isoform type-2, 1,2-ETHANEDIOL, 7-chloranyl-5-(2-cyclopropylpyridin-3-yl)-8-fluoranyl-2-methyl-pyrazolo[3,4-c]quinolin-4-one, ... (7 entities in total)
• 機能のキーワード: transferase, one-carbon metabolism, metal-binding, inhibitor complex
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46716.30

構造登録者

Tong, S.L.,Zhang, G.P. (登録日: 2023-12-05, 公開日: 2024-06-26)

主引用文献

Zheng, J.,Zhang, T.,Tong, S.,Liu, T.,Cui, J.,Xu, H.,Hu, D.,Shen, Y.,Yin, Y.,Zhao, D.,Tan, C.,Dong, X.,Chen, J.,Ji, F.,Tong, C.,Li, J.J.,Li, J.,Zhang, G.
Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy.
J.Med.Chem., 67:9431-9446, 2024

PubMed Abstract: Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound , which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, demonstrates excellent brain exposure with a of 0.64 in rats.

PubMed: 38818879
DOI: 10.1021/acs.jmedchem.4c00552

実験手法

X-RAY DIFFRACTION (1.12 Å)