Chevillet, John R and Park, Gemma J and Bedalov, Antonio and Simon, Julian A and Vasioukhin, Valeri I (2008) Identification and characterization of small-molecule inhibitors of hepsin. Molecular cancer therapeutics, 7 (10). pp. 3343-3351. ISSN 1535-7163
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Abstract
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.
| Item Type: | Article or Abstract |
|---|---|
| Additional Information: | This article is available to subscribers only via the URL above for the first 12 months following publication. |
| DOI: | 10.1158/1535-7163.MCT-08-0446 |
| PubMed ID: | 18852137 |
| NIHMSID: | NIHMS92708 |
| PMCID: | PMC2659609 |
| Grant Numbers: | R01 CA129132-01A1, T32 CA009657-18, R01 CA102365-05 |
| Keywords or MeSH Headings: | Cell Line, Tumor; Drug Screening Assays, Antitumor; Enzyme Inhibitors/analysis/chemistry/pharmacology/toxicity; Humans; Protein Processing, Post-Translational/drug effects; Protein Structure, Tertiary; Recombinant Proteins/chemistry/pharmacology; Serine Endopeptidases/metabolism; Small Molecule Libraries/analysis/chemistry/pharmacology/toxicity; |
| Subjects: | Diseases > Solid tumors > Prostate cancer Therapeutics > Drug Therapy |
| Depositing User: | Library Staff |
| Date Deposited: | 11 Feb 2009 23:07 |
| Last Modified: | 14 Feb 2012 14:42 |
| URI: | http://authors.fhcrc.org/id/eprint/250 |
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