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

Salamouni, Nehad S. El; Buckley, Benjamin J.; Ranson, Marie; Kelso, Michael J.; Yu, Haibo

doi:10.1007/s12551-021-00921-7

Cited by 7 publications

(12 citation statements)

References 139 publications

(217 reference statements)

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“…82,85 Desirable uPA inhibitors for an improved PK profile would therefore include scaffolds with less basic groups (pK a < 9) that can retain the crucial salt-bridge interaction. A comprehensive review of early small-molecule inhibitors of uPA is provided in El Salamouni et al 86 Currently, the only small-molecule uPA inhibitor to enter Phase 2 clinical trials is RHB-107 (also known as Mesupron, upamostat, WX-671), which was developed by Heidelberg Pharma AG (previously WILEX AG) and is now licensed by RedHill Biopharma Ltd. 87 RHB-107 in combination with Gemcitabine (Gem) was evaluated in a Phase 2 proof-ofconcept study in patients with locally advanced, nonresectable pancreatic cancer and reported good tolerability and a greater response rate for 1-year survival; however, no statistical significance was found for progression-free survival and overall survival (ClinicalTrials.gov identifier: NCT00499265). 88 In a separate Phase 2 trial, the combination of RHB-107 and capecitabine improved median progression-free survival (8.3 months) compared to capecitabine alone (4.3 months) in HER-2 negative breast cancer patients who had received prior adjuvant chemotherapy (ClinicalTrials.gov Identifier: NCT00615940).…”

Section: Upa-targeted Therapeuticsmentioning

confidence: 99%

“…As such, most uPA inhibitors have historically featured positively charged and highly basic (p K a > 11) aryl amidine or guanidine functional moieties that, although create the essential salt-bridge interaction with Asp189, confer poor oral bioavailability and an undesirable PK profile. , Desirable uPA inhibitors for an improved PK profile would therefore include scaffolds with less basic groups (p K a < 9) that can retain the crucial salt-bridge interaction. A comprehensive review of early small-molecule inhibitors of uPA is provided in El Salamouni et al…”

Section: Current Status and Challenges For Upa-targeted Therapeuticsmentioning

confidence: 99%

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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%

Section: Current Status and Challenges For Upa-targeted Therapeuticsmentioning

confidence: 99%

Recent Advances in Targeting the Urokinase Plasminogen Activator with Nanotherapeutics

2023

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“…A comprehensive review of earlier developmental work on selective small molecule uPA inhibitors is provided in Rockway et al [ 217 ]. Despite these advancements, most of these compounds have not progressed to clinical trials for several reasons, including high hydrophobicity of compounds, poor bioavailability, as well as challenges relating to species specificity where several inhibitors modelled on human uPAR fail to inhibit the murine receptor, limiting preliminary validation in preclinical mouse models [ 218 , 219 ]. From a medicinal chemistry perspective, a shared feature of TLSPs and a critical target for drug design of uPA inhibitors is a deep S1 binding pocket that contains a highly conserved and negatively charged Asp189 at its base, which forms a salt-bridge interaction with positively charged side chains of P1 amino acid residues [ 220 , 221 ].…”

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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“…54,70−73 It has been reported that NHE1 is among the potential targets for the observed anticancer effects of amiloride and its analogues. 54,57,60,61 To begin, we constructed…”

Section: ■ Introductionmentioning

confidence: 99%

“…38 Ligands Bound to NHE1 Maintain Key Interactions with Asp267 and Glu346. As we are interested in developing amiloride analogues as potential inhibitors for NHE1, 54 we performed MD simulations of six NHE1 inhibitors to study their binding and interactions. These inhibitors are cariporide 1, amiloride 2, 5-(N,Nhexamethylene)amiloride (HMA) 3, and three 6-substituted HMA derivatives�the benzofuranyl 4, pyrimidinyl 5, and 4methoxypyrimidinyl 6 analogues.…”

Section: ■ Introductionmentioning

confidence: 99%

Ion Transport and Inhibitor Binding by Human NHE1: Insights from Molecular Dynamics Simulations and Free Energy Calculations

El Salamouni,

Buckley,

Lee

et al. 2024

J. Phys. Chem. B

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The human Na + /H + exchanger (NHE1) plays a crucial role in maintaining intracellular pH by regulating the electroneutral exchange of a single intracellular H + for one extracellular Na + across the plasma membrane. Understanding the molecular mechanisms governing ion transport and the binding of inhibitors is of importance in the development of anticancer therapeutics targeting NHE1. In this context, we performed molecular dynamics (MD) simulations based on the recent cryoelectron microscopy (cryo-EM) structures of outward-and inward-facing conformations of NHE1. These simulations allowed us to explore the dynamics of the protein, examine the ion-translocation pore, and confirm that Asp267 is the ion-binding residue. Our free energy calculations did not show a significant difference between Na + and K + binding at the ion-binding site. Consequently, Na + over K + selectivity cannot be solely explained by differences in ion binding. Our MD simulations involving NHE1 inhibitors (cariporide and amiloride analogues) maintained stable interactions with Asp267 and Glu346. Our study highlights the importance of the salt bridge between the positively charged acylguanidine moiety and Asp267, which appears to play a role in the competitive inhibitory mechanism for this class of inhibitors. Our computational study provides a detailed mechanistic interpretation of experimental data and serves the basis of future structure-based inhibitor design.

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

Cited by 7 publications

References 139 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

Ion Transport and Inhibitor Binding by Human NHE1: Insights from Molecular Dynamics Simulations and Free Energy Calculations

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