Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 10, Pages 4335-4347Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01698
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Funding
- Innovate UK (Department for Business, Energy & Industrial Strategy)
- Pfizer Ltd. (Ramsgate Road, Sandwich, Kent, U.K.)
- UCB Pharma (208 Bath Road, Slough, Berkshire, U.K)
- Academy of Finland Organization
- TEKES Organization
- HiLIFE Organization
- Finnish Cancer Organization
- Doctoral Program in Biomedicine (DPBM)
- Biomedicum Helsinki Foundation
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Hepsin is a membrane-anchored serine protease whose role in hepatocyte growth factor (HGF) signaling and epithelial integrity makes it a target of therapeutic interest in carcinogenesis and metastasis. Using an integrated design, synthesis, and screening platform, we were able to rapidly develop potent and selective inhibitors of hepsin. In progressing from the initial hit 7 to compound 53, the ICs, value against hepsin was improved from similar to 1 mu M to 22 nM, and the selectivity over urokinase-type plasminogen activator (uPA) was increased from 30-fold to >6000-fold. Subsequent in vitro ADMET profiling and cellular studies confirmed that the leading compounds are useful tools for interrogating the role of hepsin in breast tumorigenesis.
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