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

Authors

Benjamin J. Buckley, University of WollongongFollow
Ashraf Abdel A. Aboelela, University of WollongongFollow
Elahe Minaei, University of WollongongFollow
Longguang Jiang, Fuzhou University
Zhihong Xu, University of New South Wales, Ingram Institute for Applied Medical Research
Umar Ali, University of WollongongFollow
Karen J. Fildes, University of WollongongFollow
Chen Cheung, University of Otago
Simon M. Cook, University of WollongongFollow
Darren Johnson, Memorial Sloan - Kettering Cancer Center
Daniel Bachovchin, Memorial Sloan - Kettering Cancer Center
Gregory Cook, University of OtagoFollow
Minoti Apte, University of New South Wales, Ingram Institute for Applied Medical Research
Mingdong Huang, Fuzhou UniversityFollow
Marie Ranson, University of WollongongFollow
Michael J. Kelso, University of WollongongFollow

RIS ID

130333

Publication Details

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.

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.

Grant Number

NHMRC/1100432