期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 18, 页码 8299-8320出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00838
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资金
- Australian National Health and Medical Research Council (NHMRC) [APP1100432]
- NIH [T32 GM115327]
- MSKCC Core Grant P30 [CA008748]
Metastasis is the cause of death in the majority (similar to 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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