LAUSR

Cathepsin D (Cath D) is overexpressed and secreted in a number of solid tumors and involved in the progress of tumor invasion, proliferation, metastasis, and apoptosis. Inhibition of Cath D is regarded as an attractive pathway for the development of novel anticancer drugs. Our previous studies revealed that tasiamide B, a cyanobacterial peptide that contained a statine‐like unit, exhibited good inhibition against Cath D and other aspartic proteases. Using this natural product as prototype, we designed and synthesized three new analogs, which bear isophthalic acid fragment at the N‐terminus and isobutyl amine (1), cyclopropyl amine (2), or 3‐methoxybenzyl amine (3) moiety at the C‐terminus. Enzymatic assays revealed that all these three compounds showed moderate‐to‐good inhibition against Cath D, with IC50s of 15, 884, and 353 nM, respectively. Notably, compound 1 showed extreme selectivity for Cath D with 576‐fold over Cath E and 554‐fold over BACE1, which could be a valuable template for the design of highly potent and selective Cath D inhibitors. Additionally, compound 1 showed moderated activity against HeLa cell lines with IC50 of 41.8 μM. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.