3GB2

GSK3beta inhibitor complex

Summary for 3GB2

• Entry DOI: 10.2210/pdb3gb2/pdb
• Related: 3F7Z 3F88
• Descriptor: 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)
• Functional Keywords: protein kinase, inhibitor, complex, atp-binding, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase, wnt signaling pathway, cdm
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P49841
• Total number of polymer chains: 1
• Total formula weight: 40424.37

Authors

Mol, C.D. (deposition date: 2009-02-18, release date: 2010-03-02, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)