Abstract
A series of inhibitors of mTOR kinase based on a quaternary-substituted dihydrofuropyrimidine was designed and synthesized. The most potent compounds in this series inhibited mTOR kinase with K(i) < 1.0 nM and were highly (>100×) selective for mTOR over the closely related PI3 kinases. Compounds in this series showed inhibition of the pathway and antiproliferative activity in cell-based assays. Furthermore, these compounds had excellent mouse PK, and showed a robust PK-PD relationship in a mouse model of cancer.
MeSH terms
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Administration, Oral
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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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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Drug Stability
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Furans / chemical synthesis*
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Furans / pharmacokinetics
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Furans / pharmacology
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Humans
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Mice
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Mice, Nude
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Models, Molecular
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Neoplasm Transplantation
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Phosphoinositide-3 Kinase Inhibitors
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rats
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Species Specificity
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Stereoisomerism
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Structure-Activity Relationship
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Furans
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Phosphoinositide-3 Kinase Inhibitors
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Pyrimidines
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TOR Serine-Threonine Kinases