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PDBsum entry 5zah
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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B.J.Buckley,
A.Aboelela,
E.Minaei,
L.X.Jiang,
Z.Xu,
U.Ali,
K.Fildes,
C.Y.Cheung,
S.M.Cook,
D.C.Johnson,
D.A.Bachovchin,
G.M.Cook,
M.Apte,
M.Huang,
M.Ranson,
M.J.Kelso.
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Ref.
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J Med Chem, 2018,
61,
8299-8320.
[DOI no: ]
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PubMed id
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Abstract
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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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