3L17

Discovery of (thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer

3L17 の概要

• エントリーDOI: 10.2210/pdb3l17/pdb
• 関連するPDBエントリー: 3L13 3L16
• 分子名称: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 4-methyl-5-(6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-4-morpholin-4-ylthieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (2 entities in total)
• 機能のキーワード: kinase, atp-binding, nucleotide-binding, transferase, pi3k-gamma p110 gamma
• 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: 111231.73

構造登録者

Murray, J.M.,Wiesmann, C. (登録日: 2009-12-10, 公開日: 2010-02-16, 最終更新日: 2023-09-06)

主引用文献

Sutherlin, D.P.,Sampath, D.,Berry, M.,Castanedo, G.,Chang, Z.,Chuckowree, I.,Dotson, J.,Folkes, A.,Friedman, L.,Goldsmith, R.,Heffron, T.,Lee, L.,Lesnick, J.,Lewis, C.,Mathieu, S.,Nonomiya, J.,Olivero, A.,Pang, J.,Prior, W.W.,Salphati, L.,Sideris, S.,Tian, Q.,Tsui, V.,Wan, N.C.,Wang, S.,Wiesmann, C.,Wong, S.,Zhu, B.Y.
Discovery of (Thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer.
J.Med.Chem., 53:1086-1097, 2010

PubMed Abstract: The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.

PubMed: 20050669
DOI: 10.1021/jm901284w

実験手法

X-RAY DIFFRACTION (3 Å)