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Identification and characterization of small-molecule inhibitors of hepsin.

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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Article URL: http://mct.aacrjournals.org/cgi/reprint/7/10/3343

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
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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