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Discovery of a Novel Aminopeptidase N Inhibitor Dino-Leucine Borate

Journal of Biosciences and Medicines 2022年第5期10卷 150-168页

作者： Yuqian Ma Minzhi Fang Yutian Li Dongqi Zhu Yanmei Du Binbin Ge Jiliang Song Xinyue Xu Chuhan Ma Xiaojun Jia Xiurong Zhang Jian Zhang Dexiu Wang Xuejian Wang School of Pharmacy Weifang Medical University Weifang China School of Basic Medicine Weifang Medical University Weifang China School of Clinical Medicine Weifang Medical University Weifang China

Aminopeptidase N(APN/CD13), a Zn2+-dependent ectopeptidase localized on the cell surface, is widely considered to influence the invasion of tumor cells. We found that boroleucine and dino-leucine borate exhibited a strong inhibitory effect on the enzyme activity of aminopeptidase N. The tested assay indicated that both compounds had an anti-proliferative effect on triple-negative breast cancer cells. Wound healing assay, migration test and matrigel-coated transwell assay showed that both boroleucine and dino-leucine borate inhibited the migration and invasion of breast cancer cells. Immunoblot analysis showed that both compounds down-regulated the expression of matrix metalloproteinase-2/9. In the capillary tube formation assay of human umbilical vein endothelial cells (HUVECs), dino-leucine borate showed better antiangiogenic activity than ubenimex even at a low concentration (10 μM). Moreover, compared with ubenimex, the anti-metastatic activity of dino-leucine borate in vivo was similar to or even better than that of ubenimex in the H22 pulmonary metastasis mouse model. In this paper, we found the novel APN inhibitors to markedly suppress the enzyme activity of APN and inhibit the migration and invasion of tumor cells in vitro and in vivo.

关键词： Aminopeptidase Inhibitor Anti-Tumor boroleucine Dino-Leucine Borate

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