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.

中文翻译：

---

树枝状大分子硫酸乙酰肝素糖代谢药：有效的乙酰肝素酶抑制剂用于抗癌治疗。

乙酰肝素酶是一种哺乳动物内切糖苷酶，可裂解硫酸乙酰肝素（HS）多糖，并有助于细胞外基质的重塑和HS结合蛋白生物利用度的调节。乙酰肝素酶在恶性肿瘤和炎症中被上调，有助于细胞迁移和信号分子的释放。它被确立为抗癌治疗的高度可药物化的细胞外靶标，但是由于成本，生产复杂性或脱靶效应，目前的化合物存在局限性。在这里，我们报告了一个新颖的，有针对性的单实体糖模拟物簇的合成库，该库具有简单的硫酸化糖。几种树状聚合物HS糖模拟物显示低nM IC ₅₀在临床开发中，乙酰肝素酶抑制作用的效力与比较化合物相当，并且在小鼠异种移植模型中有效抑制人骨髓瘤肿瘤细胞的转移和生长。重要的是，它们缺乏抗凝活性和细胞毒性，并且还抑制血管生成。它们为抗癌和更广泛的治疗应用提供了新的候选类别，可从靶向乙酰肝素酶抑制中受益。