We present here the structure-based design and synthesis of new cathepsin B inhibitors using the cocrystal structure of 5-nitro-8-hydroxyquinoline in the cathepsin B active site. A focused library of over 50 compounds was prepared by modifying positions 5, 7,and 8 of the parent compound nitroxoline. The kinetic parameters and modes of inhibition were characterized, and the selectivities of the most promising inhibitors were determined. The best performing inhibitor 17 was effective in cell-based in vitro models of tumor invasion, where it significantly abrogated invasion of MCF-10A neoT cells.
COBISS.SI-ID: 3370865
The cytoskeletal protein talin, an actin- and beta-integrin tail-binding protein,plays an important role in cell migration by promoting integrin activation and focal adhesion formation. Here, we show that talin is a substrate for cathepsin H (CtsH), a lysosomal cysteine protease with a strong aminopeptidase activity. The attenuation of CtsH aminopeptidase activity by a specific inhibitor or siRNA-mediated silencing significantly reduced the migration of PC-3 cells on fibronectin and invasion through Matrigel. We propose that CtsH-mediated processing of talin might promote cancer cell progression by affecting integrin activation and adhesion strength. Because of the structure similariry between cathepsins B and H nitroxoline derivatives have to be tested also to cathepsin H.
COBISS.SI-ID: 3390321