4FLH

Crystal structure of human PI3K-gamma in complex with AMG511

4FLH の概要

• エントリーDOI: 10.2210/pdb4flh/pdb
• 関連するPDBエントリー: 4DK5 4F1S 4FJY 4FJZ
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, 4-(2-[(5-fluoro-6-methoxypyridin-3-yl)amino]-5-{(1R)-1-[4-(methylsulfonyl)piperazin-1-yl]ethyl}pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine, ... (4 entities in total)
• 機能のキーワード: p110, phosphotransferase, cancer, p85, phosphorylation, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : P48736
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 110725.89

構造登録者

Whittington, D.A.,Tang, J.,Yakowec, P. (登録日: 2012-06-14, 公開日: 2012-08-29, 最終更新日: 2024-02-28)

主引用文献

Norman, M.H.,Andrews, K.L.,Bo, Y.Y.,Booker, S.K.,Caenepeel, S.,Cee, V.J.,D'Angelo, N.D.,Freeman, D.J.,Herberich, B.J.,Hong, F.T.,Jackson, C.L.,Jiang, J.,Lanman, B.A.,Liu, L.,McCarter, J.D.,Mullady, E.L.,Nishimura, N.,Pettus, L.H.,Reed, A.B.,Miguel, T.S.,Smith, A.L.,Stec, M.M.,Tadesse, S.,Tasker, A.,Aidasani, D.,Zhu, X.,Subramanian, R.,Tamayo, N.A.,Wang, L.,Whittington, D.A.,Wu, B.,Wu, T.,Wurz, R.P.,Yang, K.,Zalameda, L.,Zhang, N.,Hughes, P.E.
Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511.
J.Med.Chem., 55:7796-7816, 2012

PubMed Abstract: The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511.

PubMed: 22897589
DOI: 10.1021/jm300846z

実験手法

X-RAY DIFFRACTION (2.6 Å)