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

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• 作者：Timothy P. Heffron ; Laurent Salphati ; Bruno Alicke ; Jonathan Cheong ; Jennafer Dotson ; Kyle Edgar ; Richard Goldsmith ; Stephen E. Gould ; Leslie B. Lee ; John D. Lesnick ; Cristina Lewis ; Chudi Ndubaku ; Jim Nonomiya ; Alan G. Olivero ; Jodie Pang ; Emile G. Plise ; Steve Sideris ; Sean Trapp ; Jeffrey Wallin ; Lan Wang ; Xiaolin Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 27, 2012
• 年：2012
• 卷：55
• 期：18
• 页码：8007-8020
• 全文大小：581K
• 年卷期：v.55,no.18(September 27, 2012)
• ISSN：1520-4804

文摘

Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3K伪 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鈥揵rain 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.