Targeting Zymogen Activation To Control the Matriptase-Prostasin Proteolytic Cascade
Abbreviated Journal Title
J. Med. Chem.
HEPATOCYTE GROWTH-FACTOR; MEMBRANE SERINE-PROTEASE; PLASMINOGEN-ACTIVATOR; STROMAL CELLS; ENDOTHELIAL-CELLS; EPITHELIAL-CELLS; BREAST-CANCER; IN-VITRO; INHIBITOR; EXPRESSION; Chemistry, Medicinal
Membrane-associated serine protease matriptase has been implicated in human diseases and might be a drug target. In the present study, a novel class of matriptase inhibitors targeting zymogen activation is developed by a combination of the screening of compound library using a cell-based matriptase activation assay and a computer-aided search of commercially available analogues of a selected compound. Four structurally related compounds are identified that can inhibit matriptase activation with IC(50) at low rnicromolar concentration in both intact-cell and cell-free systems, suggesting that these inhibitors target the matriptase autoactivation machinery rather than the intracellular signaling pathways. These activation inhibitors can also inhibit prostasin activation, a downstream event that occurs in lockstep with matriptase activation. In contrast, the matriptase catalytic inhibitor CVS-3983 at a concentration 300-fold higher than its K(i) fails to inhibit activation of either protease. Our results suggest that inhibiting matriptase activation is an efficient way to control matriptase function.
Journal of Medicinal Chemistry
"Targeting Zymogen Activation To Control the Matriptase-Prostasin Proteolytic Cascade" (2011). Faculty Bibliography 2010s. 2130.