Abstract
Asparagine endopeptidase (AEP), also called legumain, is highly expressed in various solid tumors, promoting cancer cell invasion, migration, and metastasis. It has been proposed to be a prognostic marker and therapeutic target for cancer treatment. However, an effective nonpeptide, small-molecule inhibitor against this protease has not yet been identified. Here we show that a family of xanthine derivatives selectively inhibit AEP and suppress matrix metalloproteinase (MMP) cleavage, leading to the inhibition of cancer metastasis. Through structure-activity relationship (SAR) analysis, we obtained an optimized lead compound (38u) that represses breast cancer invasion and migration. Chronic treatment of nude mice, which had been inoculated with MDA-MB-231 cells, with inhibitor 38u via oral administration robustly inhibits breast cancer lung metastasis in a dose-dependent manner, associated with blockade of MMP-2 by AEP. Therefore, our study supports that 38u might act as a potent and specific AEP inhibitor useful for cancer treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Breast / drug effects
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Breast / metabolism
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Breast / pathology
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Cell Line, Tumor
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / pharmacology
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Cysteine Proteinase Inhibitors / therapeutic use*
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Female
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Humans
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Lung / drug effects
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Lung / metabolism
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Lung / pathology
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Lung Neoplasms / prevention & control*
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Lung Neoplasms / secondary*
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Mice
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Mice, Nude
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Neoplasm Invasiveness / pathology
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Neoplasm Invasiveness / prevention & control
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Structure-Activity Relationship
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Xanthine / chemistry
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Xanthine / pharmacology
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Xanthine / therapeutic use*
Substances
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Antineoplastic Agents
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Cysteine Proteinase Inhibitors
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Xanthine
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Cysteine Endopeptidases
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asparaginylendopeptidase