Potent, Selective, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin Kinase Domain Exhibiting Single Agent Antiproliferative Activity
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- 作者：Michael F. T. Koehler ; Philippe Bergeron ; Elizabeth Blackwood ; Krista K. Bowman ; Yung-Hsiang Chen ; Gauri Deshmukh ; Xiao Ding ; Jennifer Epler ; Kevin Lau ; Leslie Lee ; Lichuan Liu ; Cuong Ly ; Shiva Malek ; Jim Nonomiya ; Jason Oeh ; Daniel F. Ortwine ; Deepak Sampath ; Steve Sideris ; Lan Trinh ; Tom Truong ; Jiansheng Wu ; Zhonghua Pei ; Joseph P. Lyssikatos
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：December 27, 2012
- 年：2012
- 卷：55
- 期：24
- 页码：10958-10971
- 全文大小：603K
- 年卷期：v.55,no.24(December 27, 2012)
- ISSN：1520-4804
文摘
Selective inhibitors of mammalian target of rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with Ki < 10 nM for the mTOR kinase and >500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway. Two compounds exhibiting suitable mouse PK were profiled in in vivo tumor models and were shown to suppress mTORC1 and mTORC2 signaling for over 12 h when dosed orally. Both compounds were additionally shown to suppress tumor growth in vivo in a PC3 prostate cancer model over a 14 day study.