Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer
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The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chemistry effort led to the discovery of an improved mTOR inhibitor 3 (Torin2), which possesses an EC[subscript 50] of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC[subscript 50]: 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compound 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compound 1.
Date issued
2011-02Department
Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research; Koch Institute for Integrative Cancer Research at MITJournal
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Citation
Liu, Qingsong et al. “Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer.” Journal of Medicinal Chemistry 54.5 (2011): 1473–1480.
Version: Author's final manuscript
ISSN
0022-2623
1520-4804