Abstract
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(50) of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC(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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Administration, Oral
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Aminopyridines / chemical synthesis*
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Aminopyridines / pharmacokinetics
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Aminopyridines / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Biological Availability
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Drug Stability
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Male
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Mice
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Mice, Inbred C57BL
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Microsomes, Liver / metabolism
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Models, Molecular
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Naphthyridines / chemical synthesis*
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Naphthyridines / pharmacokinetics
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Naphthyridines / pharmacology
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Structure-Activity Relationship
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
Substances
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1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
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9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one
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Aminopyridines
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Antineoplastic Agents
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Naphthyridines
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TOR Serine-Threonine Kinases