학술논문
Potent, Selective, andOrally Bioavailable Inhibitorsof the Mammalian Target of Rapamycin Kinase Domain Exhibiting SingleAgent Antiproliferative Activity.
Document Type
Article
Author
Koehler, Michael F. T.; Bergeron, Philippe; Blackwood, Elizabeth; Bowman, Krista K.; Chen, Yung-Hsiang; 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
Source
Subject
*KINASE inhibitors
*DRUG bioavailability
*RAPAMYCIN
*TARGETED drug delivery
*INHIBITION of cellular proliferation
*HETEROCYCLIC compounds
*PYRIMIDINES
*PHOSPHOINOSITIDES
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Language
ISSN
0022-2623
Abstract
Selective inhibitors of mammalian target of rapamycin(mTOR) kinasebased upon saturated heterocycles fused to a pyrimidine core weredesigned and synthesized. Each series produced compounds with Ki< 10 nM for the mTOR kinase and >500-foldselectivity over closely related PI3 kinases. This potency translatedinto strong pathway inhibition, as measured by phosphorylation ofmTOR substrate proteins and antiproliferative activity in cell lineswith a constitutively active PI3K pathway. Two compounds exhibitingsuitable mouse PK were profiled in in vivo tumor models and were shownto suppress mTORC1 and mTORC2 signaling for over 12 h when dosed orally.Both compounds were additionally shown to suppress tumor growth invivo in a PC3 prostate cancer model over a 14 day study. [ABSTRACT FROM AUTHOR]