Identification and characterization of small-molecule inhibitors of hepsin.

Publication Type:

Journal Article


Molecular cancer therapeutics, Volume 7, Issue 10, p.3343-51 (2008)


2008, Cell Line, Tumor, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Human Biology Division, Humans, Protein Processing, Post-Translational, Protein Structure, Tertiary, Recombinant Proteins, Scientific Imaging Core Facility, Serine Endopeptidases, Shared Resources, Small Molecule Libraries


Hepsin is a type II transmembrane serine protease overexpressed in the majority of human prostate cancers. We recently demonstrated that hepsin promotes prostate cancer progression and metastasis and thus represents a potential therapeutic target. Here we report the identification of novel small-molecule inhibitors of hepsin catalytic activity. We utilized purified human hepsin for high-throughput screening of established drug and chemical diversity libraries and identified sixteen inhibitory compounds with IC(50) values against hepsin ranging from 0.23-2.31 microM and relative selectivity of up to 86-fold or greater. Two compounds are orally administered drugs established for human use. Four compounds attenuated hepsin-dependent pericellular serine protease activity in a dose dependent manner with limited or no cytotoxicity to a range of cell types. These compounds may be used as leads to develop even more potent and specific inhibitors of hepsin to prevent prostate cancer progression and metastasis.