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Dendrimer Heparan Sulfate Glycomimetics: Potent Heparanase Inhibitors for Anticancer Therapy

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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 Turnbull
Heparanase 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.8b00909

Journal title

ACS Chemical Biology

Volume

13

Issue

12

Publication date

2018-12-21

Pagination

3236-3242

Publisher

American Chemical Society (ACS)

Publication status

Published

Online publication date

2018-11-27

ISSN

1554-8929

eISSN

1554-8937

Language

en