Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors
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- 作者：Emily A. Peterson ; Aless ; ro A. Boezio ; Paul S. Andrews ; Christiane M. Boezio ; Tammy L. Bush ; Alan C. Cheng ; Deborah Choquette ; James R. Coats ; Adria E. Colletti ; Katrina W. Copel ; Michelle DuPont ; Russell Graceffa ; Barbara Grubinska ; Joseph L. Kim ; Richard T. Lewis ; Jingzhou Liu ; Erin L. Mullady ; Michele H. Potashman ; Karina Romero ; Paul L. Shaffer ; et al.
- 关键词：mTOR ; Kinase inhibitor ; Oncology ; Imidazopyridine ; Imidazopyridazine
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：1 August, 2012
- 年：2012
- 卷：22
- 期：15
- 页码：4967-4974
- 全文大小：814 K
文摘
mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.