ArticleJournal of medicinal chemistry2018
6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer.
Article in Journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
35 citing papers in PubMed, 68 citations in OpenAlex.
- Amiloride sensitizes prostate cancer cells to the reversible tyrosine kinase inhibitor lapatinib by modulating Erbb3 subcellular localization.Cellular and molecular life sciences : CMLS · 2024Article
- PAI-1 deficiency drives pulmonary vascular smooth muscle remodeling and pulmonary hypertension.American journal of physiology. Lung cellular and molecular physiology · 2024Article
- A novel lipophilic amiloride derivative efficiently kills chemoresistant breast cancer cells.Scientific reports · 2024Article
- Pancreatic Cancer Treatment Targeting the HGF/c-MET Pathway: The MEK Inhibitor Trametinib.Cancers · 2024Review
- Ligand-Based Design of Selective Peptidomimetic uPA and TMPRSS2 Inhibitors with Arg Bioisosteres.International journal of molecular sciences · 2024Article
- Hexamethylene amiloride binds the SARS-CoV-2 envelope protein at the protein-lipid interface.Protein science : a publication of the Protein Society · 2023Article
- Antifungal activity of 6-substituted amiloride and hexamethylene amiloride (HMA) analogs.Frontiers in cellular and infection microbiology · 2023Article
- 6-Furopyridine Hexamethylene Amiloride Is a Non-Selective P2X7 Receptor Antagonist.Biomolecules · 2022Article
- In Silico Evaluation of Hexamethylene Amiloride Derivatives as Potential Luminal Inhibitors of SARS-CoV-2 E Protein.International journal of molecular sciences · 2022Article
- The Remaining Conundrum of the Role of the NaReviews in cardiovascular medicine · 2022Review
- A tEMTing target? Clinical and experimental evidence for epithelial-mesenchymal transition in the progression of cutaneous squamous cell carcinoma (a scoping systematic review).Discover oncology · 2022Article
- ENaC activation by proteases.Acta physiologica (Oxford, England) · 2022Review
- Structure-Activity Relationship of Benzofuran Derivatives with Potential Anticancer Activity.Cancers · 2022Review
- An amiloride derivative is active against the FCommunications biology · 2022Article
- Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity.Biophysical reviews · 2022Review
- The Urokinase Plasminogen Activation System in Pancreatic Cancer: Prospective Diagnostic and Therapeutic Targets.Biomolecules · 2022Review
- Role of Serine Proteases at the Tumor-Stroma Interface.Frontiers in immunology · 2022Review
- The prospect of tumor microenvironment-modulating therapeutical strategies.Frontiers in oncology · 2022Review
- Role of pH Regulatory Proteins and Dysregulation of pH in Prostate Cancer.Reviews of physiology, biochemistry and pharmacology · 2022Article
- Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: Key role of the urokinase plasminogen activator (PLAU).Frontiers in immunology · 2022Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 4 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.