5ZA7

uPA-HMA

Summary for 5ZA7

• Entry DOI: 10.2210/pdb5za7/pdb
• Descriptor: Urokinase-type plasminogen activator chain B, 3-azanyl-5-(azepan-1-yl)-N-[bis(azanyl)methylidene]-6-chloranyl-pyrazine-2-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: urokinase, amiloride, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 28850.21

Authors

Buckley, B.J.,Jiang, L.G.,Huang, M.D.,Kelso, M.J.,Ranson, M. (deposition date: 2018-02-06, release date: 2018-12-19, Last modification date: 2024-11-20)

Primary citation

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.
6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer.
J. Med. Chem., 61:8299-8320, 2018

PubMed 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.

PubMed: 30130401
DOI: 10.1021/acs.jmedchem.8b00838

Experimental method

X-RAY DIFFRACTION (1.7 Å)