Abstract
PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Drug Design
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Female
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HCT116 Cells
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HT29 Cells
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology*
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Male
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Mice, Inbred BALB C
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Mice, Nude
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Molecular Docking Simulation
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
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Phosphoinositide-3 Kinase Inhibitors / chemistry
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Phosphoinositide-3 Kinase Inhibitors / pharmacokinetics
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Phosphoinositide-3 Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Rats, Sprague-Dawley
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
Substances
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Imidazoles
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyridines
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imidazopyridine
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MTOR protein, human
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TOR Serine-Threonine Kinases