4DK5

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

4DK5 の概要

• エントリーDOI: 10.2210/pdb4dk5/pdb
• 分子名称: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, 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, ... (4 entities in total)
• 機能のキーワード: phosphotransferase, cancer, p85-alpha, p85-beta, ras, 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: 110540.75

構造登録者

Whittington, D.A.,Tang, J.,Yakowec, P. (登録日: 2012-02-03, 公開日: 2012-05-16, 最終更新日: 2023-09-13)

主引用文献

Smith, A.L.,D'Angelo, N.D.,Bo, Y.Y.,Booker, S.K.,Cee, V.J.,Herberich, B.,Hong, F.T.,Jackson, C.L.,Lanman, B.A.,Liu, L.,Nishimura, N.,Pettus, L.H.,Reed, A.B.,Tadesse, S.,Tamayo, N.A.,Wurz, R.P.,Yang, K.,Andrews, K.L.,Whittington, D.A.,McCarter, J.D.,Miguel, T.S.,Zalameda, L.,Jiang, J.,Subramanian, R.,Mullady, E.L.,Caenepeel, S.,Freeman, D.J.,Wang, L.,Zhang, N.,Wu, T.,Hughes, P.E.,Norman, M.H.
Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases.
J.Med.Chem., 55:5188-5219, 2012

PubMed Abstract: A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.

PubMed: 22548365
DOI: 10.1021/jm300184s

実験手法

X-RAY DIFFRACTION (2.95 Å)