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

Journal Article


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.

Authors


  •   Buckley, Benjamin J.
  •   Aboelela, Ashraf A. (external author)
  •   Minaei, Elahe
  •   Jiang, Longguang (external author)
  •   Xu, Zhihong (external author)
  •   Ali, Umar (external author)
  •   Fildes, Karen J.
  •   Cheung, Chen (external author)
  •   Cook, Simon M. (external author)
  •   Johnson, Darren (external author)
  •   Bachovchin, Daniel (external author)
  •   Cook, Gregory (external author)
  •   Apte, Minoti (external author)
  •   Huang, Mingdong (external author)
  •   Ranson, Marie
  •   Kelso, Michael J.

Publication Date


  • 2018

Citation


  • Buckley, B. J., Aboelela, A., Minaei, E., Jiang, L. X., Xu, Z., Ali, U., Fildes, K., Cheung, C., Cook, S. M., Johnson, D. C., Bachovchin, D. A., Cook, G. M., Apte, M., Huang, M., Ranson, M. & Kelso, M. J. (2018). 6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer. Journal of Medicinal Chemistry, 61 (18), 8299-8320.

Scopus Eid


  • 2-s2.0-85053197916

Number Of Pages


  • 21

Start Page


  • 8299

End Page


  • 8320

Volume


  • 61

Issue


  • 18

Place Of Publication


  • United States

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.

Authors


  •   Buckley, Benjamin J.
  •   Aboelela, Ashraf A. (external author)
  •   Minaei, Elahe
  •   Jiang, Longguang (external author)
  •   Xu, Zhihong (external author)
  •   Ali, Umar (external author)
  •   Fildes, Karen J.
  •   Cheung, Chen (external author)
  •   Cook, Simon M. (external author)
  •   Johnson, Darren (external author)
  •   Bachovchin, Daniel (external author)
  •   Cook, Gregory (external author)
  •   Apte, Minoti (external author)
  •   Huang, Mingdong (external author)
  •   Ranson, Marie
  •   Kelso, Michael J.

Publication Date


  • 2018

Citation


  • Buckley, B. J., Aboelela, A., Minaei, E., Jiang, L. X., Xu, Z., Ali, U., Fildes, K., Cheung, C., Cook, S. M., Johnson, D. C., Bachovchin, D. A., Cook, G. M., Apte, M., Huang, M., Ranson, M. & Kelso, M. J. (2018). 6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer. Journal of Medicinal Chemistry, 61 (18), 8299-8320.

Scopus Eid


  • 2-s2.0-85053197916

Number Of Pages


  • 21

Start Page


  • 8299

End Page


  • 8320

Volume


  • 61

Issue


  • 18

Place Of Publication


  • United States