Systematic evaluation of structure–property relationships and pharmacokinetics in 6-(hetero)aryl-substituted matched pair analogs of amiloride and 5-(N,N-hexamethylene)amiloride

Buckley, Benjamin J.; Aboelela, Ashraf; Majed, Hiwa; Bujaroski, Richard S.; White, Karen L.; Powell, Andrew K.; Wen, Wang; Katneni, Kasiram; Saunders, Jessica; Shackleford, David M.; Charman, Susan A.; Cook, Gregory M.; Kelso, Michael J.; Ranson, Marie

doi:10.1016/j.bmc.2021.116116

Cited by 13 publications

(13 citation statements)

References 51 publications

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“…99 Despite remarkable results for uPA inhibition across multiple cancer types, alongside demonstrated in vivo efficacy showing a strong antimetastatic response, these amiloride analogues were limited by poor PK properties, including low membrane permeability, poor oral bioavailability and rapid hepatic and renal clearance. 100 Encapsulating uPA inhibitors within nanoparticle (NP)-based drug delivery systems (NDDS) to optimize the bioavailability and PK of these compounds remains to be fully explored and could thus serve as an exciting opportunity to develop novel protease-targeted cancer nanotherapies with improved tolerability.…”

Section: Upa-targeted Therapeuticsmentioning

confidence: 99%

Recent Advances in Targeting the Urokinase Plasminogen Activator with Nanotherapeutics

2023

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The aberrant proteolytic landscape of the tumor microenvironment is a key contributor of cancer progression. Overexpression of urokinase plasminogen activator (uPA) and/or its associated cell-surface receptor (uPAR) in tumor versus normal tissue is significantly associated with worse clinicopathological features and poorer patient survival across multiple cancer types. This is linked to mechanisms that facilitate tumor cell invasion and migration, via direct and downstream activation of various proteolytic processes that degrade the extracellular matrix�ultimately leading to metastasis. Targeting uPA has thus long been considered an attractive anticancer strategy. However, poor bioavailability of several uPA-selective smallmolecule inhibitors has limited early clinical progress. Nanodelivery systems have emerged as an exciting method to enhance the pharmacokinetic (PK) profile of existing chemotherapeutics, allowing increased circulation time, improved bioavailability, and targeted delivery to tumor tissue. Combining uPA inhibitors with nanoparticle-based delivery systems thus offers a remarkable opportunity to overcome existing PK challenges associated with conventional uPA inhibitors, while leveraging potent candidates into novel targeted nanotherapeutics for an improved anticancer response in uPA positive tumors.

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Section: Upa-targeted Therapeuticsmentioning

confidence: 99%

Recent Advances in Targeting the Urokinase Plasminogen Activator with Nanotherapeutics

2023

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“…The same study found that treatment with selected uPA inhibitors showed reduced to complete inhibition of liver metastases in an orthotopic xenograft mouse model of PDAC compared with mice treated with first-line treatment gemcitabine. More recently, the authors reported cell surface inhibition of HMW human uPA activity in highly invasive triple-negative metastatic breast cancer cells, known to strongly express uPA and uPAR, and reported rodent PK data for the most promising analogues [ 227 , 228 ].…”

Section: The Upas As a Target For Pancreatic Cancer Therapymentioning

confidence: 99%

The Urokinase Plasminogen Activation System in Pancreatic Cancer: Prospective Diagnostic and Therapeutic Targets

2022

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Pancreatic cancer is a highly aggressive malignancy that features high recurrence rates and the poorest prognosis of all solid cancers. The urokinase plasminogen activation system (uPAS) is strongly implicated in the pathophysiology and clinical outcomes of patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic cancers. Overexpression of the urokinase-type plasminogen activator (uPA) or its cell surface receptor uPAR is a key step in the acquisition of a metastatic phenotype via multiple mechanisms, including the increased activation of cell surface localised plasminogen which generates the serine protease plasmin. This triggers multiple downstream processes that promote tumour cell migration and invasion. Increasing clinical evidence shows that the overexpression of uPA, uPAR, or of both is strongly associated with worse clinicopathological features and poor prognosis in PDAC patients. This review provides an overview of the current understanding of the uPAS in the pathogenesis and progression of pancreatic cancer, with a focus on PDAC, and summarises the substantial body of evidence that supports the role of uPAS components, including plasminogen receptors, in this disease. The review further outlines the clinical utility of uPAS components as prospective diagnostic and prognostic biomarkers for PDAC, as well as a rationale for the development of novel uPAS-targeted therapeutics.

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“…In the clinic, amiloride's maximum recommended dose is limited to 20 mg/day due to the risks of hyperkalemia and cardiac arrhythmias (Sun & Sever 2020). In animal models, anticancer/metastasis effects require administration of relatively high doses of amiloride (>5 mg/kg/day), suggesting amiloride is unlikely to produce meaningful anticancer effects when given at safe doses in humans (Buckley et al 2021a;Matthews et al 2011a). Thus, Selective Optimisation of a Side Activity (SOSA) approach (Wermuth 2006) represented an attractive strategy to optimise amiloride into a more potent, orally active uPA inhibitor for use in cancer.…”

Section: S1β Pocketmentioning

confidence: 99%

Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity

et al. 2022

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Systematic evaluation of structure–property relationships and pharmacokinetics in 6-(hetero)aryl-substituted matched pair analogs of amiloride and 5-(N,N-hexamethylene)amiloride

Cited by 13 publications

References 51 publications

Recent Advances in Targeting the Urokinase Plasminogen Activator with Nanotherapeutics

Recent Advances in Targeting the Urokinase Plasminogen Activator with Nanotherapeutics

The Urokinase Plasminogen Activation System in Pancreatic Cancer: Prospective Diagnostic and Therapeutic Targets

Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity

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