Phospshoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors: Discovery and Structure鈥揂ctivity Relationships of a Series of Quinoline and Quinoxaline Derivatives

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• 作者：Nobuko Nishimura ; Aaron Siegmund ; Longbin Liu ; Kevin Yang ; Marian C. Bryan ; Kristin L. Andrews ; Yunxin Bo ; Shon K. Booker ; Sean Caenepeel ; Daniel Freeman ; Hongyu Liao ; John McCarter ; Erin L. Mullady ; Tisha San Miguel ; Raju Subramanian ; Nuria Tamayo ; Ling Wang ; Douglas A. Whittington ; Leeanne Zalameda ; Nancy Zhang ; Paul E. Hughes ; Mark H. Norman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4735-4751
• 全文大小：1296K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

The phosphoinositide 3-kinase (PI3K) family catalyzes the ATP-dependent phosphorylation of the 3鈥?hydroxyl group of phosphatidylinositols and plays an important role in cell growth and survival. There is abundant evidence demonstrating that PI3K signaling is dysregulated in many human cancers, suggesting that therapeutics targeting the PI3K pathway may have utility for the treatment of cancer. Our efforts to identify potent, efficacious, and orally available PI3K/mammalian target of rapamycin (mTOR) dual inhibitors resulted in the discovery of a series of substituted quinolines and quinoxalines derivatives. In this report, we describe the structure鈥揳ctivity relationships, selectivity, and pharmacokinetic data of this series and illustrate the in vivo pharmacodynamic and efficacy data for a representative compound.