Inhibitors of HGFA, matriptase, and hepsin serine proteases: A nonkinase strategy to block cell signaling in cancer

Zhenfu Han, Peter K.W. Harris, Darin E. Jones, Ryan Chugani, Tommy Kim, Manjula Agarwal, Wei Shen, Scott A. Wildman, James W. Janetka

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Hepatocyte growth factor activators (HGFA), matriptase, and hepsin are S1 family trypsin-like serine proteases. These proteases proteolytically cleave the single-chain zymogen precursors, pro-HGF (hepatocyte growth factor), and pro-MSP (macrophage stimulating protein) into active heterodimeric forms. HGF and MSP are activating ligands for the oncogenic receptor tyrosine kinases (RTKs), c-MET and RON, respectively. We have discovered the first substrate-based ketothiazole inhibitors of HGFA, matriptase and hepsin. The compounds were synthesized using a combination of solution and solid-phase peptide synthesis (SPPS). Compounds were tested for protease inhibition using a kinetic enzyme assay employing fluorogenic peptide substrates. Highlighted HGFA inhibitors are Ac-KRLR-kt (5g), Ac-SKFR-kt (6c), and Ac-SWLR-kt (6g) with Kis = 12, 57, and 63 nM, respectively. We demonstrated that inhibitors block the conversion of native pro-HGF and pro-MSP by HGFA with equivalent potency. Finally, we show that inhibition causes a dose-dependent decrease of c-MET signaling in MDA-MB-231 breast cancer cells. This preliminary investigation provides evidence that HGFA is a promising therapeutic target in breast cancer and other tumor types driven by c-MET and RON.

Original languageEnglish
Pages (from-to)1219-1224
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number11
StatePublished - Nov 13 2014


  • HGF
  • HGFA
  • MSP
  • RON
  • breast cancer
  • c-MET
  • cell signaling
  • growth factor
  • hepsin
  • inhibitor
  • ketothiazole
  • kinase
  • matriptase
  • peptidomimetic
  • serine protease
  • solid-phase peptide synthesis


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