Mechanism-Based Inhibitors Of Hgfa, Matriptase And Hepsin For Breast Cancer Treatment

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Hepatocyte Growth Factor Activator (HGFA) is a member of the S1 family of trypsin-like serine proteases. Its biological function is to proteolytically process the inactive single-chain zymogen precursors of the receptor tyrosine kinase ligands HGF (hepatocyte growth factor) and MSP (macrophage stimulating protein) resulting in formation of their active heterodimeric forms which initiate ligand-dependent c-MET and RON kinase cell signaling, respectively. We have discovered the first small molecular weight mechanism-based ketothiazole inhibitors of HGFA. The compounds were evaluated for HGFA, matriptase and hepsin inhibition in a protease competition assay using a chromogenic peptide substrate. We have identified several sub-micromolar inhibitors of HGFA and demonstrate they inhibit conversion of the native pro-HGF and pro-MSP substrates into active heterodimers. Finally, we show that HGFA inhibitors cause a dose-dependent decrease c-MET phosphorylation in invasive MDA-MB-231 breast cancer cells. This investigation provides preliminary validation of HGFA as a novel therapeutic target for breast cancer. These initial peptides serve as templates for lead optimization and the structure-based design of other small-molecule inhibitors. Optimized inhibitors will be used to study the role of HGFA in the regulation of growth factors, kinase receptor activation, cell signaling, invasion, and breast cancer metastasis. Citation Format: James Janetka, Zhenfu Han, Peter Harris, Scott Wildman. Mechanism-based inhibitors of HGFA, matriptase and hepsin for breast cancer treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2523. doi:10.1158/1538-7445.AM2014-2523