The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3-Kinase α

被引：45

作者：

Heffron, Timothy P. ^{[1
]}

Salphati, Laurent ^{[1
]}

Alicke, Bruno ^{[1
]}

Cheong, Jonathan ^{[1
]}

Dotson, Jennafer ^{[1
]}

Edgar, Kyle ^{[1
]}

Goldsmith, Richard ^{[1
]}

Gould, Stephen E. ^{[1
]}

Lee, Leslie B. ^{[1
]}

Lesnick, John D. ^{[1
]}

Lewis, Cristina ^{[1
]}

Ndubaku, Chudi ^{[1
]}

Nonomiya, Jim ^{[1
]}

Olivero, Alan G. ^{[1
]}

Pang, Jodie ^{[1
]}

Plise, Emile G. ^{[1
]}

Sideris, Steve ^{[1
]}

Trapp, Sean ^{[1
]}

Wallin, Jeffrey ^{[1
]}

Wang, Lan ^{[1
]}

Zhang, Xiaolin ^{[1
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 18期

关键词：

P-GLYCOPROTEIN; PI3K/MTOR INHIBITOR; CANCER; POTENT; PREDICTION; DISCOVERY; ALIGNMENT; GDC-0941; KINASE; CORE;

D O I：

10.1021/jm300867c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3K alpha has received significant attention for its potential in cancer therapy. While the PI3K pathway is a well-established and widely pursued target for the treatment of many cancer types due to the high frequency of abnormal PI3K signaling, glioblastoma multiforme (GBM) is particularly relevant because the pathway is implicated in more than 80% of GBM cases. Herein, we report the identification of PI3K inhibitors designed to cross the blood-brain barrier (BBB) to engage their target where GBM tumors reside. We leveraged our historical experience with PI3K inhibitors to identify correlations between physicochemical properties and transporter efflux as well as metabolic stability to focus the selection of molecules for further study.

引用

页码：8007 / 8020

页数：14

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