Recent progress on inhibitors of the type II transmembrane serine proteases, hepsin, matriptase and matriptase-2

Future Med Chem. 2019 Apr;11(7):743-769. doi: 10.4155/fmc-2018-0446. Epub 2019 Apr 4.


Members of the type II transmembrane serine proteases (TTSP) family play a vital role in cell growth and development but many are also implicated in disease. Two of the well-studied TTSPs, matriptase and hepsin proteolytically process multiple protein substrates such as the inactive single-chain zymogens pro-HGF and pro-macrophage stimulating protein into the active heterodimeric forms, HGF and macrophage stimulating protein. These two proteases also have many other substrates which are associated with cancer and tumor progression. Another related TTSP, matriptase-2 is expressed in the liver and functions by regulating iron homoeostasis through the cleavage of hemojuvelin and thus is implicated in iron overload diseases. In the present review, we will discuss inhibitor design strategy and Structure activity relationships of TTSP inhibitors, which have been reported in the literature.

Keywords: HGF; HGFA; MET; MSP; RON; TTSP; Type II transmembrane serine protease; benzamidine; hepsin; inhibitor; ketobenzothiazole; ketothiazole; matriptase; matriptase-2; peptide; structure–activity relationship.

Publication types

  • Review

MeSH terms

  • Benzamidines / chemistry*
  • Benzamidines / metabolism
  • Drug Discovery
  • GPI-Linked Proteins / metabolism
  • Hemochromatosis Protein / metabolism
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Membrane Proteins / antagonists & inhibitors
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Protein Precursors / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Serine Endopeptidases / metabolism
  • Serine Proteases / metabolism
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / metabolism
  • Signal Transduction
  • Structure-Activity Relationship
  • Thiazoles / chemistry*


  • Benzamidines
  • GPI-Linked Proteins
  • HJV protein, human
  • Hemochromatosis Protein
  • Membrane Proteins
  • Protein Precursors
  • Proto-Oncogene Proteins
  • Serine Proteinase Inhibitors
  • Thiazoles
  • macrophage stimulating protein
  • pro-hepatocyte growth factor
  • Hepatocyte Growth Factor
  • Serine Proteases
  • Serine Endopeptidases
  • hepsin
  • matriptase
  • matriptase 2