期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：31
DOI：10.1073/pnas.2203167119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Cancer growth is accompanied by changes to the extracellular environment of tumors, which aids the proliferation and spread of cancer cells. Cancer-associated extracellular matrix changes include excessive degradation of heparan sulfate carbohydrates, promoting metastatic spread by multiple mechanisms. Heparanase is the main human enzyme responsible for extracellular heparan sulfate breakdown and strongly drives metastasis when overexpressed. Few effective heparanase inhibitors are known, and the most effective molecules to date possess nondrug-like structures with multiple off-target effects. We have carried out structure-guided development of heparanase inhibitors, which covalently bind to the enzyme active site to cause irreversible inhibition. These inhibitors are heparanase specific and reduce metastasis in animal models with comparable efficacy to current “best-in-class” compounds.
Heparan sulfate proteoglycans (HSPGs) mediate essential interactions throughout the extracellular matrix (ECM), providing signals that regulate cellular growth and development. Altered HSPG composition during tumorigenesis strongly aids cancer progression. Heparanase (HPSE) is the principal enzyme responsible for extracellular heparan sulfate catabolism and is markedly up-regulated in aggressive cancers. HPSE overactivity degrades HSPGs within the ECM, facilitating metastatic dissemination and releasing mitogens that drive cellular proliferation. Reducing extracellular HPSE activity reduces cancer growth, but few effective inhibitors are known, and none are clinically approved. Inspired by the natural glycosidase inhibitor cyclophellitol, we developed nanomolar mechanism-based, irreversible HPSE inhibitors that are effective within physiological environments. Application of cyclophellitol-derived HPSE inhibitors reduces cancer aggression in cellulo and significantly ameliorates murine metastasis. Mechanism-based irreversible HPSE inhibition is an unexplored anticancer strategy. We demonstrate the feasibility of such compounds to control pathological HPSE-driven malignancies.
