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ACS Med Chem Lett. 2014 Oct 9;5(11):1219-24. doi: 10.1021/ml500254r. eCollection 2014 Nov 13.

Inhibitors of HGFA, Matriptase, and Hepsin Serine Proteases: A Nonkinase Strategy to Block Cell Signaling in Cancer.

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Department of Biochemistry and Molecular Biophysics, Alvin J. Siteman Cancer Center, and Department of Medicine, Oncology Division, Washington University School of Medicine , 660 South Euclid Avenue, St. Louis, Missouri 63110, United States.


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 K is = 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.


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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