Abstract
Recently, the phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) have been considered as promising targets for the treatment of cancer. Herein, we synthesized a series of N-(5-(quinolin-6-yl)pyridin-3-yl)benzenesulfonamides as novel PI3K/mTOR dual inhibitors for cancer therapy. In the biological evaluation, compound 17e was identified as a potent PI3K/mTOR dual inhibitor, which significantly inhibit Class I PI3Ks, mTOR and phosphorylation of pAkt(Ser473) at low nanomolar level. Moreover, 17e display high potency against PC-3 cells (IC50 = 80 nM) in the anti-proliferative assay, and showed acceptable pharmacokinetic properties in vivo.
Keywords:
Cancer; Inhibitor; PI3K; mTOR.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Animals
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Benzenesulfonamides
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chemistry Techniques, Synthetic
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Drug Design*
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Humans
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Male
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Mice
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Molecular Docking Simulation
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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 Conformation
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Sulfonamides / chemical synthesis*
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Sulfonamides / metabolism
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology*
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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Xenograft Model Antitumor Assays
Substances
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Sulfonamides
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TOR Serine-Threonine Kinases