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.
Benjamin J Buckley  1  2 ,  Ashraf Aboelela  1  2 ,  Elahe Minaei  1  2 ,  Longguang X Jiang  3 ,  Zhihong Xu  4 ,  Umar Ali  1  2 ,  Karen Fildes  2  5 ,  Chen-Yi Cheung  6 ,  Simon M Cook  2 ,  Darren C Johnson  7 ,  Daniel A Bachovchin  7  8 ,  Gregory M Cook  6 ,  Minoti Apte  4 ,  Mingdong Huang  3 ,  Marie Ranson  1  2 ,  Michael J Kelso  1  2
Affiliations
  • 1. Molecular Horizons and School of Chemistry & Molecular Bioscience , University of Wollongong , Wollongong , NSW 2522 , Australia.
  • 2. Illawarra Health & Medical Research Institute , Wollongong , NSW 2522 , Australia.
  • 3. National Joint Biomedical Engineering Research Centre on Photodynamic Technologies , Fuzhou University , Fujian 350116 , China.
  • 4. Pancreatic Research Group, South Western Sydney Clinical School , University of New South Wales, and Ingham Institute for Applied Medical Research , Liverpool , NSW 2170 , Australia.
  • 5. Graduate School of Medicine , University of Wollongong , Wollongong , NSW 2522 , Australia.
  • 6. Department of Microbiology and Immunology , University of Otago , Otago 9016 , New Zealand.
  • 7. Tri-Institutional PhD Program in Chemical Biology , Memorial Sloan Kettering Cancer Center , New York , New York 10065 , United States.
  • 8. Chemical Biology Program , Memorial Sloan Kettering Cancer Center , New York , New York 10065 , United States.
PMID: 30130401 DOI: 10.1021/acs.jmedchem.8b00838
Abstract

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.