Proceedings of the National Academy of Sciences of the United States of America · 2022
Mechanism-based heparanase inhibitors reduce cancer metastasis in vivo.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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de Boer Casper, Armstrong Zachary, Lit Vincent A J, Barash Uri, Ruijgrok Gijs, Boyango Ilanit, Weitzenberg Merle M, Schröder Sybrin P, Sarris Alexi J C, Meeuwenoord Nico J, Bule Pedro, Kayal Yasmine, Ilan Neta, Codée Jeroen D C, Vlodavsky Israel, Overkleeft Herman S, Davies Gideon J, Wu Liang
Аннотация
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.