Abstract
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.
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 / chemistry
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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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Female
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Humans
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Male
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Mice
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Mice, Nude
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Molecular Docking Simulation
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Multiprotein Complexes / antagonists & inhibitors*
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Neoplasm Transplantation
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Prostatic Neoplasms
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Quinazolines / chemical synthesis*
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Quinazolines / chemistry
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Quinazolines / pharmacology
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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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Multiprotein Complexes
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Phosphoinositide-3 Kinase Inhibitors
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Pyrimidines
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Pyrroles
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Quinazolines
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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TOR Serine-Threonine Kinases