Identification and characterization of small-molecule inhibitors of hepsin.
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.
Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N. C3-168, Seattle, WA 98109-1024, USA.
John R
JR
Chevillet
Gemma J
GJ
Park
Antonio
A
Bedalov
Julian A
JA
Simon
Valeri I
VI
Vasioukhin
D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D012697:Serine Endopeptidases; C055645:hepsin