3QAQ

Crystal structure of PI3K-gamma in complex with triazine-benzimidazole 1

3QAQ の概要

• エントリーDOI: 10.2210/pdb3qaq/pdb
• 関連するPDBエントリー: 3QAR
• 分子名称: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, [(4-{2-[(3-hydroxyphenyl)amino]-1H-benzimidazol-1-yl}-1,3,5-triazin-2-yl)amino]acetonitrile, ... (4 entities in total)
• 機能のキーワード: inhibitor, p110, kinase, transferase, atp binding, p84, p101, transferase-transferase inhibitor complex, transferase/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: 110470.60

構造登録者

Whittington, D.A.,Tang, J.,Yakowec, P. (登録日: 2011-01-11, 公開日: 2011-03-30, 最終更新日: 2023-09-13)

主引用文献

Peterson, E.A.,Andrews, P.S.,Be, X.,Boezio, A.A.,Bush, T.L.,Cheng, A.C.,Coats, J.R.,Colletti, A.E.,Copeland, K.W.,Dupont, M.,Graceffa, R.,Grubinska, B.,Harmange, J.C.,Kim, J.L.,Mullady, E.L.,Olivieri, P.,Schenkel, L.B.,Stanton, M.K.,Teffera, Y.,Whittington, D.A.,Cai, T.,La, D.S.
Discovery of triazine-benzimidazoles as selective inhibitors of mTOR.
Bioorg.Med.Chem.Lett., 21:2064-2070, 2011

PubMed Abstract: mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC(50) of 0.41 μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model.

PubMed: 21376583
DOI: 10.1016/j.bmcl.2011.02.007

実験手法

X-RAY DIFFRACTION (2.9 Å)