6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease

Buckley, Benjamin J.; Majed, Hiwa; Aboelela, Ashraf; Minaei, Elahe; Jiang, Longguang; Fildes, Karen; Cheung, Chen‐Yi; Johnson, Darren C.; Bachovchin, Daniel A.; Cook, Gregory M.; Huang, Mingdong; Ranson, Marie; Kelso, Michael J.

doi:10.1016/j.bmcl.2019.126753

Cited by 27 publications

(51 citation statements)

References 30 publications

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“…For example the commonly used uncoupler, carbonyl cyanide m -chlorophenyl hydrazone (CCCP), is toxic to both prokaryote and eukaryote cells (22). Here, we report that two recently reported 6-substituted amiloride analogues, BB2-50F and HM2-16F(23, 24) (Fig. 1A), inhibit motility in known phenamil-resistant strains and affect both Na + - and H + -powered flagellar motors.…”

Section: Introductionsupporting

confidence: 52%

“…This restricts the possibility that they will be targets for efflux pumps and thus will remain effective as anti-motility comppounds against multi-drug resistant bacteria that rely on such pumps (43). Furthermore, considering these compounds have some known anti-metastatic effects (23,24), these compounds could potentially show promise not only in the treatment of disease but also simultaneously in reducing the virulence of infections that may arise during treatment.…”

Section: Discussionmentioning

confidence: 99%

“…5-( N,N -hexamethylene)amiloride (HMA) (UOW), HM2-16F (UOW) and BB2-50F (UOW) were synthesised as described previously (23, 24). Phenamil methanesulfonate salt (Sigma-Aldrich), Chloramphenicol (Sigma-Aldrich), Dimethyl sulfoxide (DMSO) (Sigma-Aldrich) and D-Arabinose (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

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Novel amiloride derivatives that inhibit bacterial motility across multiple strains and stator types

Islam

Bae

Ishida

et al. 2021

Preprint

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The bacterial flagellar motor (BFM) is a protein complex that confers motility to cells and contributes to survival and virulence. The BFM consists of stators that are ion-selective membrane protein complexes and a rotor that directly connects to a large filament, acting as a propeller. The stator complexes couple ion transit across the membrane to torque that drives rotation of the motor. The most common ion gradients that drive BFM rotation are protons (H+) and sodium ions (Na+). The sodium-powered stators, like those in the PomAPomB stator complex of Vibrio spp, can be inhibited by sodium channel inhibitors, in particular, by phenamil, a potent and widely used inhibitor. However, relatively few new sodium-motility inhibitors have been described since the discovery of phenamil. In this study, we discovered two motility inhibitors HM2-16F and BB2-50F from a small library of previously reported amiloride derivatives. Using a tethered cell assay, we showed that both HM2-16F and BB2-50F had inhibition comparable to that of phenamils on Na+ driven motors at matching concentrations, with an additional ability to inhibit rotation in H+ driven motors. The two compounds did not exhibit adverse effects on bacterial growth at the motility-inhibiting concentration of 10 uM, however toxicity was seen for BB2-50F at 100 uM. We performed higher resolution measurements to examine rotation inhibition at moderate (1 um polystyrene bead) and low loads (60 nm gold bead) and in both the presence and absence of stators. These measurements suggested that the compounds did not inhibit rotation via direct association with the stator, in contrast to the established mode of action of phenamil. Overall, HM2-16F and BB2-50F showed reversible inhibition of motility across a range of loads, in both Na+ and H+ stator types, and in pathogenic and non-pathogenic strains.

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Section: Introductionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

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Novel amiloride derivatives that inhibit bacterial motility across multiple strains and stator types

Islam

Bae

Ishida

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Our initial efforts to increase uPA potency by adding substituted amines to position 5 on the pyrazine core were largely unsuccessful, producing only modest improvements (~2-fold) relative to amiloride [ 25 ]. More recent work with matched series of 6-substituted 5-( N , N -hexamethylene)amiloride (HMA) [ 26 ] and amiloride (i.e., 5-NH 2 ) [ 27 ] analogs targeting the uPA S1β subsite resulted in uPA potency gains exceeding 100-fold. Lead compounds from these series showed low nM uPA potency, high selectivity for uPA across the serine hydrolase superfamily, no ENaC activity, and in vivo anti-metastatic effects in xenografted mouse models of lung and pancreatic cancer [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…More recent work with matched series of 6-substituted 5-( N , N -hexamethylene)amiloride (HMA) [ 26 ] and amiloride (i.e., 5-NH 2 ) [ 27 ] analogs targeting the uPA S1β subsite resulted in uPA potency gains exceeding 100-fold. Lead compounds from these series showed low nM uPA potency, high selectivity for uPA across the serine hydrolase superfamily, no ENaC activity, and in vivo anti-metastatic effects in xenografted mouse models of lung and pancreatic cancer [ 26 , 27 ]. Activity against NHE1 was not examined in these studies.…”

Section: Introductionmentioning

confidence: 99%

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

Buckley

Kumar

Aboelela

et al. 2021

IJMS

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The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co‑screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5,715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.

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A tEMTing target? Clinical and experimental evidence for epithelial-mesenchymal transition in the progression of cutaneous squamous cell carcinoma (a scoping systematic review)

et al. 2022

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Cutaneous squamous cell carcinoma (cSCC) is a disease with globally rising incidence and poor prognosis for patients with advanced or metastatic disease. Epithelial-mesenchymal transition (EMT) is a driver of metastasis in many carcinomas, and cSCC is no exception. We aimed to provide a systematic overview of the clinical and experimental evidence for EMT in cSCC, with critical appraisal of type and quality of the methodology used. We then used this information as rationale for potential drug targets against advanced and metastatic cSCC. All primary literature encompassing clinical and cell-based or xenograft experimental studies reporting on the role of EMT markers or related signalling pathways in the progression of cSCC were considered. A screen of 3443 search results yielded 86 eligible studies comprising 44 experimental studies, 22 clinical studies, and 20 studies integrating both. From the clinical studies a timeline illustrating the alteration of EMT markers and related signalling was evident based on clinical progression of the disease. The experimental studies reveal connections of EMT with a multitude of factors such as genetic disorders, cancer-associated fibroblasts, and matrix remodelling via matrix metalloproteinases and urokinase plasminogen activator. Additionally, EMT was found to be closely tied to environmental factors as well as to stemness in cSCC via NFκB and β-catenin. We conclude that the canonical EGFR, canonical TGF-βR, PI3K/AKT and NFκB signalling are the four signalling pillars that induce EMT in cSCC and could be valuable therapeutic targets. Despite the complexity, EMT markers and pathways are desirable biomarkers and drug targets for the treatment of advanced or metastatic cSCC. Graphical Abstract

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6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease

Cited by 27 publications

References 30 publications

Novel amiloride derivatives that inhibit bacterial motility across multiple strains and stator types

Novel amiloride derivatives that inhibit bacterial motility across multiple strains and stator types

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

A tEMTing target? Clinical and experimental evidence for epithelial-mesenchymal transition in the progression of cutaneous squamous cell carcinoma (a scoping systematic review)

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