Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349

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• 作者：Zhonghua Pei ; Elizabeth Blackwood ; Lichuan Liu ; Shiva Malek ; Marcia Belvin ; Michael F. T. Koehler ; Daniel F. Ortwine ; Huifen Chen ; Frederick Cohen ; Jane R. Kenny ; Philippe Bergeron ; Kevin Lau ; Cuong Ly ; Xianrui Zhao ; Anthony A. Estrada ; Tom Truong ; Jennifer A. Epler ; Jim Nonomiya ; Lan Trinh ; Steve Sideris ; John Lesnick ; Linda Bao ; Ulka Vijapurkar ; Sophie Mukadam ; Suzanne Tay ; Gauri Deshmukh ; Yung-Hsiang Chen ; Xiao Ding ; Lori S. Friedman ; Joseph P. Lyssikatos
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：4
• 期：1
• 页码：103-107
• 全文大小：307K
• 年卷期：v.4,no.1(January 10, 2013)
• ISSN：1948-5875

文摘

Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.

Keywords:

Mammalian target of rapamycin; mTOR; TDI; urea bioisostere