Abstract
The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.
MeSH terms
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Adenosine Triphosphate / physiology*
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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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Binding Sites
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Carbamates / chemical synthesis
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Carbamates / chemistry
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Carbamates / pharmacology
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Cell Line, Tumor
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Class Ib Phosphatidylinositol 3-Kinase
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Crystallography, X-Ray
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Drug Design
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / chemistry
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Isoenzymes / chemistry
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Mice
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Mice, Nude
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Microsomes / metabolism
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Models, Molecular
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Phosphatidylinositol 3-Kinases / chemistry
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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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
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Urea / analogs & derivatives
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Urea / chemical synthesis
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Urea / chemistry
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Urea / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Carbamates
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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Pyrazoles
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Pyrimidines
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Adenosine Triphosphate
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Urea
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mTOR protein, mouse
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Class Ib Phosphatidylinositol 3-Kinase
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Pik3cg protein, mouse
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases