10.1021/acs.jmedchem.7b00228.s002 Qi Qi Qi Qi Obiamaka Obianyo Obiamaka Obianyo Yuhong Du Yuhong Du Haian Fu Haian Fu Shiyong Li Shiyong Li Keqiang Ye Keqiang Ye Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis American Chemical Society 2017 AEP breast cancer lung metastasis represses breast cancer invasion Asparagine Endopeptidase Inhibits Cancer Metastasis Asparagine endopeptidase SAR cancer treatment inhibitor MDA-MB -231 cells MMP cancer cell invasion 2017-08-17 21:04:57 Dataset https://acs.figshare.com/articles/dataset/Blockade_of_Asparagine_Endopeptidase_Inhibits_Cancer_Metastasis/5324287 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 (<b>38u</b>) that represses breast cancer invasion and migration. Chronic treatment of nude mice, which had been inoculated with MDA-MB-231 cells, with inhibitor <b>38u</b> 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 <b>38u</b> might act as a potent and specific AEP inhibitor useful for cancer treatment.