Dendrimer Heparan Sulfate Glycomimetics: Potent Heparanase Inhibitors for Anticancer Therapy

Zubkova, Olga V, Ahmed, Yassir A, Guimond, Scott E, Noble, Sophia-Louise, Miller, John Holmes, Smith, Raymond Alexander Alfred, Nurcombe, Victor, Tyler, Peter C, Weissmann, Marina, Vlodavsky, Israel
et al (show 1 more authors) (2018) Dendrimer Heparan Sulfate Glycomimetics: Potent Heparanase Inhibitors for Anticancer Therapy. ACS Chemical Biology, 13 (12). 3236 - 3242.

[img] Text
Dendrimer HS Glycomimetics Potent heparanase inhibitors Manuscript_ACS Chem Biol.docx - Accepted Version

Download (11MB)


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 IC50 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.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 07 Dec 2018 12:35
Last Modified: 08 Sep 2022 00:12
DOI: 10.1021/acschembio.8b00909
Related URLs: