Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR

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• 作者：Timothy P. Heffron ; Chudi O. Ndubaku ; Laurent Salphati ; Bruno Alicke ; Jonathan Cheong ; Joy Drobnick ; Kyle Edgar ; Stephen E. Gould ; Leslie B. Lee ; John D. Lesnick ; Cristina Lewis ; Jim Nonomiya ; Jodie Pang ; Emile G. Plise ; Steve Sideris ; Jeffrey Wallin ; Lan Wang ; Xiaolin Zhang ; Alan G. Olivero
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：7
• 期：4
• 页码：351-356
• 全文大小：375K
• 年卷期：0
• ISSN：1948-5875

文摘

Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood–brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules were ultimately deemed not suitable for clinical development due to projected poor metabolic stability in humans. We, therefore, extended our studies to identify a BBB penetrating inhibitor of PI3K that was also projected to be metabolically stable in human. These efforts required identification of a distinct scaffold for PI3K inhibitors relative to our previous efforts and ultimately resulted in the identification of GDC-0084 (16). The discovery and preclinical characterization of this molecule are described within.