Hepsin, a type II transmembrane serine protease, is an attractive protein as a potential therapeutic and diagnostic biomarker for prostate cancer because it is highly up-regulated in prostate cancer and promotes both progression and metastasis. Starting from the reported tetrapeptide hepsin inhibitor Ac-KQLR-ketothiazole (kt) (1), we investigated the minimal structural requirements for hepsin inhibitory activity by truncating amino acids at the N-terminus. The kt and ketobenzothiazole (kbt) dipeptide analogs Ac-LR-kt (3) and Ac-LR-kbt (15) were found to be potent hepsin inhibitors, exhibiting Ki values of 22nM and 3nM, respectively. The present work suggests that LR-containing dipeptide molecules could be useful as lead compounds for the development of novel hepsin inhibitors.
Keywords: Dipeptides; Hepsin; Prostate cancer; Serine protease.
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