7RWG

"Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor AGI-43192

7RWG の概要

• エントリーDOI: 10.2210/pdb7rwg/pdb
• 関連するPDBエントリー: 7KCC 7RW5 7RW7
• 分子名称: S-adenosylmethionine synthase isoform type-2, S-ADENOSYLMETHIONINE, CHLORIDE ION, ... (7 entities in total)
• 機能のキーワード: methionine adenosyltransferase, sam, allosteric inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• 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: 45128.89

構造登録者

Jin, L.,Padyana, A.K. (登録日: 2021-08-19, 公開日: 2022-03-23, 最終更新日: 2023-10-18)

主引用文献

Li, M.,Konteatis, Z.,Nagaraja, N.,Chen, Y.,Zhou, S.,Ma, G.,Gross, S.,Marjon, K.,Hyer, M.L.,Mandley, E.,Lein, M.,Padyana, A.K.,Jin, L.,Tong, S.,Peters, R.,Murtie, J.,Travins, J.,Medeiros, M.,Liu, P.,Frank, V.,Judd, E.T.,Biller, S.A.,Marks, K.M.,Sui, Z.,Reznik, S.K.
Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads.
J.Med.Chem., 65:4600-4615, 2022

PubMed Abstract: Inhibition of the -adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A (MAT2A), has received significant interest in the field of medicinal chemistry due to its implication as a synthetic lethal target in cancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novel MAT2A inhibitors with distinct properties that may enhance their utility in treating patients. Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, , to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, , and a potent, but limited brain-penetrant compound, . We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS).

PubMed: 35293760
DOI: 10.1021/acs.jmedchem.1c01595

実験手法

X-RAY DIFFRACTION (0.97 Å)