2. Academic Validation
  3. 6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer

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

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.

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