upamostat and Lung-Neoplasms

Metastasis is the cause of death in the majority (∼90%) of malignant cancers. The oral potassium-sparing diuretic amiloride and its 5-substituted derivative 5 -N, N-(hexamethylene)amiloride (HMA) reportedly show robust antitumor/metastasis effects in multiple in vitro and animal models. These effects are likely due, at least in part, to inhibition of the urokinase plasminogen activator (uPA), a key protease determinant of cell invasiveness and metastasis. This study reports the discovery of 6-substituted HMA analogs that show nanomolar potency against uPA, high selectivity over related trypsin-like serine proteases, and minimal inhibitory effects against epithelial sodium channels (ENaC), the diuretic and antikaliuretic target of amiloride. Reductions in lung metastases were demonstrated for two analogs in a late-stage experimental mouse metastasis model, and one analog completely inhibited formation of liver metastases in an orthotopic xenograft mouse model of pancreatic cancer. The results support further evaluation of 6-substituted HMA derivatives as uPA-targeting anticancer drugs.

Topics: Amiloride; Animals; Antineoplastic Agents; Cell Movement; Cell Proliferation; Crystallography, X-Ray; Diuresis; Diuretics; Drug Discovery; Female; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Models, Molecular; Molecular Structure; Pancreatic Neoplasms; Potassium; Protein Conformation; Sodium; Structure-Activity Relationship; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator; Xenograft Model Antitumor Assays