Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis

• Type of Material: Article
• Authors: Qi Qi, Emory University; Obiamaka Obianyo, Emory University; Yuhong Du, Emory University; Haian Fu, Emory University; Shiyong Li, Emory University; Keqiang Ye, Emory University
• Language: English
• Date: 2017-09-14
• Publisher: American Chemical Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Chemical Society.
• Final Published Version (URL): http://dx.doi.org/10.1021/acs.jmedchem.7b00228
• Title of Journal or Parent Work: Journal of Medicinal Chemistry
• ISSN: 0022-2623
• Volume: 60
• Issue: 17
• Start Page: 7244
• End Page: 7255
• Grant/Funding Information: H.F. is a GRA/Georgia Cancer Coalition Distinguished Cancer Scholar.; This work is supported by a grant from National Institute of Health (RO1, CA186918) to K.Y.
• Keywords: BREAST-CANCER; MATRIX METALLOPROTEINASE-2; Life Sciences & Biomedicine; EXTRACELLULAR-MATRIX; TUMOR-ASSOCIATED MACROPHAGES; CELL INVASION; Pharmacology & Pharmacy; ORAL BIOAVAILABILITY; PROGNOSTIC-FACTOR; ACTIVATION; MAMMALIAN LEGUMAIN; Chemistry, Medicinal; Science & Technology; LEGUMAIN EXPRESSION
• Research Categories: Health Sciences, Pathology; Biology, General; Health Sciences, Medicine and Surgery

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 cance r 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.