3D0E

Crystal structure of human Akt2 in complex with GSK690693

3D0E の概要

• エントリーDOI: 10.2210/pdb3d0e/pdb
• 分子名称: RAC-beta serine/threonine-protein kinase, 4-{2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[(3S)-piperidin-3-ylmethoxy]-1H-imidazo[4,5-c]pyridin-4-yl}-2-methylbut-3 -yn-2-ol (3 entities in total)
• 機能のキーワード: human, akt2, inhibitor, atp-binding, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase, transferase inhibitor
• 由来する生物種: Homo sapiens
• 細胞内の位置: Cytoplasm: P31751
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 78995.99

構造登録者

Concha, N.O.,Smallwood, A. (登録日: 2008-05-01, 公開日: 2008-10-21, 最終更新日: 2024-10-16)

主引用文献

Heerding, D.A.,Rhodes, N.,Leber, J.D.,Clark, T.J.,Keenan, R.M.,Lafrance, L.V.,Li, M.,Safonov, I.G.,Takata, D.T.,Venslavsky, J.W.,Yamashita, D.S.,Choudhry, A.E.,Copeland, R.A.,Lai, Z.,Schaber, M.D.,Tummino, P.J.,Strum, S.L.,Wood, E.R.,Duckett, D.R.,Eberwein, D.,Knick, V.B.,Lansing, T.J.,McConnell, R.T.,Zhang, S.,Minthorn, E.A.,Concha, N.O.,Warren, G.L.,Kumar, R.
Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.
J.Med.Chem., 51:5663-5679, 2008

PubMed Abstract: Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC 50 values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3beta. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3beta phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.

PubMed: 18800763
DOI: 10.1021/jm8004527

実験手法

X-RAY DIFFRACTION (2 Å)