Dendrimer Heparan Sulfate Glycomimetics: Potent Heparanase Inhibitors for Anticancer Therapy

Abstract

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.

The Heparan Sulfate Sulfotransferases HS2ST1 and HS3ST2 Are Novel Regulators of Breast Cancer Stem-Cell Properties

“…Our results furthermore show that the overexpression of HS2ST1 and HS3ST2 significantly alters several CSC-related characteristics in breast cancer cells in general, which is worthy of future evaluation in more complex in vivo systems. Finally, our data open a perspective for manipulating the CSC phenotype with drugs modulating HS either in a general way, or in a sequence-specific manner ( Zubkova et al, 2018 ; Vitale et al, 2019 ; Espinoza-Sánchez and Götte, 2020 ).…”

Heparanase: A Challenging Cancer Drug Target

“…Recently dendrimer glycomimetics that are heparanase enzymatic activity inhibitors were developed (112). The rationale being that the avidity of weak interactions, of the type mediated by sugar fragments binding a protein, is significantly enhanced if multiple copies of the sugar units are displayed on a chemically defined scaffold.…”

“…However, no modeling or structural data were provided to verify this suggestion. This compound was shown to inhibit tumor growth and metastasis in a mouse xenograft model with human myeloma cells (112), but no other activities described for heparanase were examined. Glycopolymers that inhibit heparanase enzymatic activity have also been prepared.…”

Bringing Heparan Sulfate Glycomics Together with Proteomics for the Design of Novel Therapeutics: A Historical Perspective

“…Tyler, Zubkova, and colleagues have recently described efficient methods for the synthesis of single chemical entity sulfated glycomimetics with their pharmacokinetics, bioavailability, and safety looking amenable for human use. In particular, we have prepared chemically defined, single‐entity polyvalent BMP‐2‐binding sequences (unpublished results) as well as heparanase inhibitors displaying simple sulfated sugars on dendritic cores . These latter inhibit heparanase, and thus angiogenesis, within low nanomolar ranges.…”

“…Heparanase‐1 is highly expressed in certain cancers, and a facilitator of angiogenesis, growth and metastasis . In recent years, as synthetic techniques have matured and become more cost‐effective, numerous HS mimetics have been synthesized and used as antagonists . A greater understanding of the structure: function relationship between HS and HS binding proteins will facilitate the synthesis of more accurate HS mimetics, potentially with fewer off‐target effects.…”