4F1S

Crystal structure of human PI3K-gamma in complex with a pyridyl-triazine-sulfonamide inhibitor

4F1S の概要

• エントリーDOI: 10.2210/pdb4f1s/pdb
• 関連するPDBエントリー: 4DK5
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, N-(5-{[3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl]amino}-2-chloropyridin-3-yl)methanesulfonamide, ... (4 entities in total)
• 機能のキーワード: phosphotransferase, lipid kinase, p85, 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: 110891.40

構造登録者

Whittington, D.A.,Tang, J.,Yakowec, P. (登録日: 2012-05-07, 公開日: 2012-08-08, 最終更新日: 2024-02-28)

主引用文献

Wurz, R.P.,Liu, L.,Yang, K.,Nishimura, N.,Bo, Y.,Pettus, L.H.,Caenepeel, S.,Freeman, D.J.,McCarter, J.D.,Mullady, E.L.,Miguel, T.S.,Wang, L.,Zhang, N.,Andrews, K.L.,Whittington, D.A.,Jiang, J.,Subramanian, R.,Hughes, P.E.,Norman, M.H.
Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold.
Bioorg.Med.Chem.Lett., 22:5714-5720, 2012

PubMed Abstract: Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC(50) and exhibited good oral bioavailability in rats (F(oral)=63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC(50)=193 nM (91 ng/mL).

PubMed: 22832322
DOI: 10.1016/j.bmcl.2012.06.078

実験手法

X-RAY DIFFRACTION (3 Å)