Furanyl-1,3-thiazol-2-yl and benzoxazol-5-yl acetic acid derivatives: novel classes of heparanase inhibitor

Courtney, Stephen M.; Hay, Philip A.; Buck, Richard T.; Colville, Claire S.; Phillips, David J.; Scopes, D. I. C.; Pollard, Faye C.; Pagé, Martin; Bennett, James M.; Hircock, Margaret L.; McKenzie, Edward A.; Bhaman, Maina; Felix, Robert; Stubberfield, Colin R.; Turner, Paul

doi:10.1016/j.bmcl.2005.03.014

Cited by 67 publications

(66 citation statements)

References 8 publications

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“…This compound functionally blocks HPSE activity (Courtney et al, 2005), and does not significantly modulate its expression. Treatment of HCE cells at 2 hpi with OGT 2115 resulted in decreased expression of pro-inflammatory factors IL-1β, IL-6, and TNF-α (Figure 6A).…”

Section: Resultsmentioning

confidence: 99%

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

et al. 2017

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Summary Herpes simplex virus type-1 (HSV-1) causes lifelong recurrent pathologies without a cure. How infection by HSV-1 triggers disease processes, especially in the immune-privileged avascular human cornea, remains a major unresolved puzzle. It has been speculated that a cornea-resident molecule must tip the balance in favor of pro-inflammatory and pro-angiogenic conditions observed with herpetic as well as non-herpetic ailments of the cornea. Here, we demonstrate that heparanase (HPSE), a host enzyme, is the molecular trigger for multiple pathologies associated with HSV-1 infection. In human corneal epithelial cells, HSV-1 infection upregulates HPSE in a manner dependent on HSV-1 infected cell protein 34.5. HPSE then relocates to the nucleus to regulate cytokine production, inhibits wound closure, enhances viral spread, and thus generates a toxic local environment. Overall, our findings implicate activated HPSE as a driver of viral pathogenesis, and call for further attention to this host protein in infection and other inflammatory disorders.

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Section: Resultsmentioning

confidence: 99%

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

et al. 2017

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“…13-O, N heterocyclic compounds have attracted increasing attention because of their potential roles in cancer. Recently, a growing number of heterocyclic compounds have been developed to inhibit HPA enzyme activity; examples include benzothiazole, benzoxazole, benzimidazole derivatives, and the imidazole pyrimidine class [15–18]. Compared to DMBO, the spiroheterocyclic HPA inhibitors we developed here have stronger inhibitory activity and increase cell apoptosis by antagonizing HPA.…”

Section: Discussionmentioning

confidence: 99%

“…The endogenous human TBP gene was used as an internal control. Results were expressed in relative amounts as described elsewhere [15]. Three separate PCR amplification reactions were run for each condition.…”

Section: Methodsmentioning

confidence: 99%

Novel 1, 3-N, O-Spiroheterocyclic compounds inhibit heparanase activity and enhance nedaplatin-induced cytotoxicity in cervical cancer cells

Song

et al. 2016

Oncotarget

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Heparanase (HPA) is an enzyme that plays an important role in cancer metastasis and angiogenesis and is a potential target for molecular treatment of tumors. We previously found that abnormally high HPA expression in cervical cancer tissues is associated with poor survival and increased lymph node metastasis. The present study was conducted to assess the utility of inhibiting HPA enzyme activity in cervical cancer treatment. Two series of 13 novel HPA inhibitors were synthesized and optimized. All tested inhibitors reduced HPA enzyme activity (IC50 values ranged from 4.47 μM to 47.19 μM) and inhibited the growth of HeLa cells (IC50 values ranged from 48.16 μM to 96.64 μM). The No. 16 inhibitor inhibited the migration and growth of HeLa and Siha cells in a dose- and time-dependent manner, and increased cell apoptosis and cell cycle G0/G1 and G2/M phase arrest, while decreasing the S phase cell population. More importantly, No. 16 sensitized cervical cancer cells to low concentrations of nedaplatin, decreased HPA, c-Myc and h-TERT levels, and increased p53 levels in HeLa and Siha cells. These results suggest that this HPA inhibitor reduced proliferation and HPA expression in cervical cancer cells by restoring p53 activity and downregulating h-TERT and c-Myc expression.

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“…Apart from HS mimetics, small molecule inhibitors, and neutralizing antibody programs were developed by various companies including Oxford Glycosciences (158, 159), Imclone Systems (138, 160), and InSight Biopharmaceuticals (139–142), but the candidates failed to reach clinical trials. Although the reasons for the limited progression through to clinical development are unknown, the lack of a crystal structure for the heparanase protein may have been one of the confounding issues.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics

Hammond¹,

et al. 2014

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Heparan sulfate proteoglycans (HSPGs) are an integral and dynamic part of normal tissue architecture at the cell surface and within the extracellular matrix. The modification of HSPGs in the tumor microenvironment is known to result not just in structural but also functional consequences, which significantly impact cancer progression. As substrates for the key enzymes sulfatases and heparanase, the modification of HSPGs is typically characterized by the degradation of heparan sulfate (HS) chains/sulfation patterns via the endo-6-O-sulfatases (Sulf1 and Sulf2) or by heparanase, an endo-glycosidase that cleaves the HS polymers releasing smaller fragments from HSPG complexes. Numerous studies have demonstrated how these enzymes actively influence cancer cell proliferation, signaling, invasion, and metastasis. The activity or expression of these enzymes has been reported to be modified in a variety of cancers. Such observations are consistent with the degradation of normal architecture and basement membranes, which are typically compromised in metastatic disease. Moreover, recent studies elucidating the requirements for these proteins in tumor initiation and progression exemplify their importance in the development and progression of cancer. Thus, as the influence of the tumor microenvironment in cancer progression becomes more apparent, the focus on targeting enzymes that degrade HSPGs highlights one approach to maintain normal tissue architecture, inhibit tumor progression, and block metastasis. This review discusses the role of these enzymes in the context of the tumor microenvironment and their promise as therapeutic targets for the treatment of cancer.

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Furanyl-1,3-thiazol-2-yl and benzoxazol-5-yl acetic acid derivatives: novel classes of heparanase inhibitor

Cited by 67 publications

References 8 publications

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

Novel 1, 3-N, O-Spiroheterocyclic compounds inhibit heparanase activity and enhance nedaplatin-induced cytotoxicity in cervical cancer cells

The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics

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