6-substituted hexamethylene amiloride (HMA) derivatives as potent and selective inhibitors of the human urokinase plasminogen activator for use in cancer Journal Article

   


Authors: Buckley, B. J.; Aboelela, A.; Minaei, E.; Jiang, L. X.; Xu, Z.; Ali, U.; Fildes, K.; Cheung, C. Y.; Cook, S. M.; Johnson, D. C.; Bachovchin, D. A.; Cook, G. M.; Apte, M.; Huang, M.; Ranson, M.; Kelso, M. J.
Article Title: 6-substituted hexamethylene amiloride (HMA) derivatives as potent and selective inhibitors of the human urokinase plasminogen activator for use in cancer
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. © 2018 American Chemical Society.
Journal Title: Journal of Medicinal Chemistry
Volume: 61
Issue: 18
ISSN: 0022-2623
Publisher: American Chemical Society  
Date Published: 2018-09-27
Start Page: 8299
End Page: 8320
Language: English
DOI: 10.1021/acs.jmedchem.8b00838
PROVIDER: scopus
PUBMED: 30130401
PMCID: PMC6290913
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85053197916&doi=10.1021%2facs.jmedchem.8b00838&partnerID=40&md5=c9540a46ca602c966dc7b4d77b4ff1d5
Notes: Article -- Export Date: 1 November 2018 -- Source: Scopus
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MSK Authors
  1. Daniel Bachovchin
    35 Bachovchin
  2. Darren Christopher Johnson
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