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

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

doi:10.1021/jm300867c.s001

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

journal contribution

posted on 2016-02-20, 10:25 authored by 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

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.