The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3‑Kinase α
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 sign...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-09, Vol.55 (18), p.8007-8020 |
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| container_title | Journal of medicinal chemistry |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1021/jm300867c |
| format | Article |
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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. 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| ispartof | Journal of medicinal chemistry, 2012-09, Vol.55 (18), p.8007-8020 |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Blood-Brain Barrier - metabolism Cell Line, Tumor Cell Proliferation - drug effects Dogs Drug Design Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Female Humans Hydrogen Bonding Madin Darby Canine Kidney Cells Mice Permeability Phosphatidylinositol 3-Kinases - antagonists & inhibitors Surface Properties |
| title | The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3‑Kinase α |
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