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.
Chevillet
John R
JR
Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N. C3-168, Seattle, WA 98109-1024, USA.
Park
Gemma J
GJ
Bedalov
Antonio
A
Simon
Julian A
JA
Vasioukhin
Valeri I
VI
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