Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors

被引：34

作者：

Dehnhardt, Christoph M. ^{[1
]}

Venkatesan, Aranapakam M. ^{[1
]}

Chen, Zecheng ^{[1
]}

Delos-Santos, Efren ^{[1
]}

Ayral-Kaloustian, Semiramis ^{[1
]}

Brooijmans, Natasja ^{[2
]}

Yu, Ker ^{[3
]}

Hollander, Irwin ^{[3
]}

Feldberg, Larry ^{[3
]}

Lucas, Judy ^{[3
]}

Mallon, Robert ^{[3
]}

机构：

[1] Pfizer, Med Chem, Pearl River, NY 10965 USA

[2] Pfizer, Computat Chem, Pearl River, NY 10965 USA

[3] Pfizer, Oncol, Pearl River, NY 10965 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 16期

关键词：

Oxatriazine scaffold; PI3K; mTOR; Akt; PKI-587; PKI-402; PHOSPHATIDYLINOSITOL 3-KINASE/MAMMALIAN TARGET; DISCOVERY; DERIVATIVES; PI3K;

D O I：

10.1016/j.bmcl.2011.06.063

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We recently described several highly potent, triazine (1) and triazolopyrimidine (2) scaffold-based, dual PI3K/mTOR-inhibitors (e.g., 1, PKI-587) that were efficacious in both in vitro and in vivo models. In order to further optimize these compounds we devised a novel series, the 2-oxatriazines, which also exhibited excellent potency and good metabolic stability. Some 2-oxatriazines showed promising in vivo biomarker suppression and induced apoptosis in the MDA-MB-361 breast cancer xenograft model. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：4773 / 4778

页数：6

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