Oral Presentation 9th General Meeting of the International Proteolysis Society 2015

Cancer associated proteases: not just the extracellular matrix anymore (#11)

James W Janetka 1
  1. Washington University, Saint Louis, MO, United States

c-MET and RON receptor tyrosine kinase pathways are clinical targets for therapeutic intervention in metastatic cancer. Co-overexpression of both kinases has been reported in several tumor types including pancreatic, prostate and breast cancer. Crosstalk between c-MET and RON and with other kinases such as EGFR and PDGFR has been recently discovered as a mechanism that tumors utilize in metastasis. While kinase inhibitors of activated c-MET, RON and downstream kinases have been developed, only limited studies have explored novel strategies which prevent kinase activation extracellularly.


The plasma HGFA and two membrane-anchored serine proteases, matriptase and hepsin proteolytic process and activate the c-MET and RON tyrosine kinase ligands, HGF and MSP, respectively. HGF and MSP are members of the plasminogen family of proteins that are secreted as inactive single-chain zymogens, pro-HGF and pro-MSP.  The processing of HGF and MSP is critical for ligand-dependent activation and cell signaling of c-MET and RON kinases. Many studies have shown HGFA, matriptase and hepsin are upregulated and aberrantly expressed in cancer cells and tumors. Proteolytic activity  is tightly regulated by the endogenous polypeptide inhibitors HAI-1 and HAI-2 which potently inhibit all three proteases. Imbalance of normal protease, HAI-1, and HAI-2 expression leads to invasive phenotypes in breast and multiple other types of cancer.


Few studies have evaluated the individual roles that HGFA, matriptase, and hepsin play in cancer development or progression or their importance in different types of cancer. Directed by structure-based drug design and peptide library substrate screening, we have synthesized  potent mechanism-based and other small-molecule inhibitors of HGFA, matriptase and hepsin. We show potent triplex inhibition effectively blocks pro-HGF and pro-MSP activation and results in decreased c-MET phophorylation, migration and invasion in breast cancer cell lines. Selective activity-based imaging probes are being developed to demonstrate their importance and regulation in cancer and metastasis.

  1. Franco, F. M., Jones, D. E., Harris, P. K., Han, Z., Wildman, S. A., Jarvis, C. M., and Janetka, J. W. (2015) Structure-based discovery of small molecule hepsin and HGFA protease inhibitors: Evaluation of potency and selectivity derived from distinct binding pockets, Bioorgan Med Chem 23, 2328-2343.
  2. Han, Z., Harris, P. K. W., Jones, D. E., Chugani, R., Kim, T., Agarwal, M., Shen, W., Wildman, S. A., and Janetka, J. W. (2014) Inhibitors of HGFA, Matriptase, and Hepsin Serine Proteases: A Nonkinase Strategy to Block Cell Signaling in Cancer, Acs Med Chem Lett 5, 1219-1224.