jm7b00228_si_002.csv (1.75 kB)
Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis
dataset
posted on 2017-08-17, 21:04 authored by Qi Qi, Obiamaka Obianyo, Yuhong Du, Haian Fu, Shiyong Li, Keqiang YeAsparagine 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.