3GB2

GSK3beta inhibitor complex

3GB2 の概要

• エントリーDOI: 10.2210/pdb3gb2/pdb
• 関連するPDBエントリー: 3F7Z 3F88
• 分子名称: Glycogen synthase kinase-3 beta, 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (3 entities in total)
• 機能のキーワード: protein kinase, inhibitor, complex, atp-binding, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase, wnt signaling pathway, cdm
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P49841
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40424.37

構造登録者

Mol, C.D. (登録日: 2009-02-18, 公開日: 2010-03-02, 最終更新日: 2024-11-06)

主引用文献

Saitoh, M.,Kunitomo, J.,Kimura, E.,Iwashita, H.,Uno, Y.,Onishi, T.,Uchiyama, N.,Kawamoto, T.,Tanaka, T.,Mol, C.D.,Dougan, D.R.,Textor, G.P.,Snell, G.P.,Takizawa, M.,Itoh, F.,Kori, M.
2-{3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl}-5-methyl-1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3beta with good brain permeability.
J.Med.Chem., 52:6270-6286, 2009

PubMed Abstract: Glycogen synthase kinase 3beta (GSK-3beta) inhibition is expected to be a promising therapeutic approach for treating Alzheimer's disease. Previously we reported a series of 1,3,4-oxadiazole derivatives as potent and highly selective GSK-3beta inhibitors, however, the representative compounds 1a,b showed poor pharmacokinetic profiles. Efforts were made to address this issue by reducing molecular weight and lipophilicity, leading to the identification of oxadiazole derivatives containing a sulfinyl group, (S)-9b and (S)-9c. These compounds exhibited not only highly selective and potent inhibitory activity against GSK-3beta but also showed good pharmacokinetic profiles including favorable BBB penetration. In addition, (S)-9b and (S)-9c given orally to mice significantly inhibited cold water stress-induced tau hyperphosphorylation in mouse brain.

PubMed: 19775160
DOI: 10.1021/jm900647e

実験手法

X-RAY DIFFRACTION (2.4 Å)