6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer

J Med Chem. 2018 Sep 27;61(18):8299-8320. doi: 10.1021/acs.jmedchem.8b00838. Epub 2018 Sep 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amiloride / chemistry
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Movement
  • Cell Proliferation
  • Crystallography, X-Ray
  • Diuresis / drug effects*
  • Diuretics / chemistry
  • Diuretics / pharmacology
  • Drug Discovery*
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / secondary
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Models, Molecular
  • Molecular Structure
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Potassium / metabolism
  • Protein Conformation
  • Sodium / metabolism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Diuretics
  • Amiloride
  • Sodium
  • Urokinase-Type Plasminogen Activator
  • Potassium