2018 Dendrimer Heparan Sulfate Glycomimetics Potent Heparanase Inhibitors ACS Chem Biol.pdf (616.55 kB)
Download fileDendrimer Heparan Sulfate Glycomimetics: Potent Heparanase Inhibitors for Anticancer Therapy
journal contribution
posted on 2021-11-18, 19:38 authored by Olga ZubkovaOlga Zubkova, YA Ahmed, SE Guimond, SL Noble, John MillerJohn Miller, RA Alfred Smith, V Nurcombe, Peter TylerPeter Tyler, M Weissmann, I Vlodavsky, JE TurnbullHeparanase is a mammalian endoglycosidase that cleaves heparan sulfate (HS) polysaccharides and contributes to remodelling of the extracellular matrix and regulation of HS-binding protein bioavailabilities. Heparanase is upregulated in malignant cancers and inflammation, aiding cell migration and the release of signaling molecules. It is established as a highly druggable extracellular target for anticancer therapy, but current compounds have limitations, because of cost, production complexity, or off-target effects. Here, we report the synthesis of a novel, targeted library of single-entity glycomimetic clusters capped with simple sulfated saccharides. Several dendrimer HS glycomimetics display low nM IC 50 potency for heparanase inhibition equivalent to comparator compounds in clinical development, and potently inhibit metastasis and growth of human myeloma tumor cells in a mouse xenograft model. Importantly, they lack anticoagulant activity and cytotoxicity, and also inhibit angiogenesis. They provide a new candidate class for anticancer and wider therapeutic applications, which could benefit from targeted heparanase inhibition.
History
Preferred citation
Zubkova, O. V., Ahmed, Y. A., Guimond, S. E., Noble, S. L., Miller, J. H., Alfred Smith, R. A., Nurcombe, V., Tyler, P. C., Weissmann, M., Vlodavsky, I. & Turnbull, J. E. (2018). Dendrimer Heparan Sulfate Glycomimetics: Potent Heparanase Inhibitors for Anticancer Therapy. ACS Chemical Biology, 13(12), 3236-3242. https://doi.org/10.1021/acschembio.8b00909Publisher DOI
Journal title
ACS Chemical BiologyVolume
13Issue
12Publication date
2018-12-21Pagination
3236-3242Publisher
American Chemical Society (ACS)Publication status
PublishedOnline publication date
2018-11-27ISSN
1554-8929eISSN
1554-8937Language
enUsage metrics
Keywords
BiomedicalBasic ScienceCancerAngiogenesis InhibitorsAnimalsAntineoplastic AgentsBiomimetic MaterialsCell Line, TumorDendrimersEnzyme InhibitorsFibroblast Growth Factor 2GlucuronidaseGlycosidesHeparitin SulfateHumansInhibitory Concentration 50MiceMolecular StructureMultiple MyelomaSignal TransductionXenograft Model Antitumor AssaysOrphan DrugRare DiseasesHematology5.1 PharmaceuticalsScience & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyBETA-SECRETASETUMOR-GROWTHCANCERPROGRESSIONMECHANISMSDISCOVERYPG545Chemical SciencesBiological SciencesOrganic Chemistry