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Heffron, Timothy P; Salphati, Laurent; Alicke, Bruno; Cheong, Jonathan; Dotson, Jennafer; Edgar, Kyle; Goldsmith, Richard; Gould, Stephen E; Lee, Leslie B; Lesnick, John D; Lewis, Cristina; Ndubaku, Chudi; Nonomiya, Jim; Olivero, Alan G; Pang, Jodie; Plise, Emile G; Sideris, Steve; Trapp, Sean; Wallin, Jeffrey; Wang, Lan; Zhang, Xiaolin
Journal of medicinal chemistry, 09/2012, Volume: 55, Issue: 18Journal Article
Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3Kα 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.
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