Abstract
Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound 18 selectively inhibited LRS-mediated mTORC1 activation and exerted specific cytotoxicity against colon cancer cells with a hyperactive mTORC1, suggesting that 18 may offer a novel treatment option for human colorectal cancer.
MeSH terms
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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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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Leucine / analogs & derivatives*
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Leucine / chemical synthesis
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Leucine / chemistry
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Leucine / pharmacology
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Leucine-tRNA Ligase / antagonists & inhibitors*
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Leucine-tRNA Ligase / metabolism
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Mechanistic Target of Rapamycin Complex 1
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Molecular Structure
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Multiprotein Complexes / antagonists & inhibitors*
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Multiprotein Complexes / metabolism
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Structure-Activity Relationship
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Multiprotein Complexes
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leucyladenylate sulfamate
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Leucine-tRNA Ligase
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Leucine