Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis
| Autor: | Haian Fu, Keqiang Ye, Obiamaka Obianyo, Shiyong Li, Qi Qi, Yuhong Du |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Mice Nude Antineoplastic Agents Breast Neoplasms Cysteine Proteinase Inhibitors Matrix metalloproteinase Legumain Xanthine Article Metastasis Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Breast cancer Cell Line Tumor Drug Discovery medicine Animals Humans Structure–activity relationship Neoplasm Invasiveness Breast Asparagine Lung biology Chemistry medicine.disease Endopeptidase Cysteine Endopeptidases 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Molecular Medicine Female |
| Zdroj: | Journal of Medicinal Chemistry. 60:7244-7255 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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