Abstract
Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3Kalpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.
MeSH terms
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Models, Molecular
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Morpholines / chemical synthesis
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Morpholines / chemistry
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Morpholines / pharmacology*
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Phosphatidylinositol 3-Kinases / chemistry
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinases / chemistry*
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Protein Kinases / metabolism
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Structure-Activity Relationship
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TOR Serine-Threonine Kinases
Substances
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Protein Kinases
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TOR Serine-Threonine Kinases