Abstract
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 language | English |
---|---|
Pages (from-to) | 1219-1224 |
Number of pages | 6 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 5 |
Issue number | 11 |
DOIs | |
State | Published - Nov 13 2014 |
Keywords
- HGF
- HGFA
- MSP
- RON
- breast cancer
- c-MET
- cell signaling
- growth factor
- hepsin
- inhibitor
- ketothiazole
- kinase
- matriptase
- peptidomimetic
- serine protease
- solid-phase peptide synthesis