【文章名】Potent, Selective, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin Kinase Domain Exhibiting Single Agent Antiproliferative Activity
Potent, Selective, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin Kinase Domain Exhibiting Single Agent Antiproliferative Activity
作者
KOEHLER MICHAEL F T; BERGERON PHILIPPE; BLACKWOOD ELIZABETH; BOWMAN KRISTA K; CHEN YUNGHSIANG; DESHMUKH GAURI; DING XIAO; EPLER JENNIFER; LAU KEVIN; LEE LESLIE; LIU LICHUAN; LY CUONG; MALEK SHIVA; NONOMIYA JIM; OEH JASON; ORTWINE DANIEL F; SAMPATH DEEPAK; SIDERIS STEVE; TRINH LAN; TRUONG TOM; WU JIANSHENG; PEI ZHONGHUA; LYSSIKATOS JOSEPH P
[摘要]：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 K-i < 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.
