Mechanism-based heparanase inhibitors reduce cancer metastasis in vivo-Reference-Cited by-同舟云学术

Mechanism-based heparanase inhibitors reduce cancer metastasis in vivo

Published:2022-07-26 Issue:31 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

de Boer Casper¹,Armstrong Zachary²³,Lit Vincent A. J.¹^ORCID,Barash Uri⁴,Ruijgrok Gijs¹^ORCID,Boyango Ilanit⁴,Weitzenberg Merle M.¹,Schröder Sybrin P.¹,Sarris Alexi J. C.¹,Meeuwenoord Nico J.¹^ORCID,Bule Pedro²⁵^ORCID,Kayal Yasmine⁴^ORCID,Ilan Neta⁴,Codée Jeroen D. C.¹,Vlodavsky Israel⁴^ORCID,Overkleeft Herman S.¹^ORCID,Davies Gideon J.²^ORCID,Wu Liang²⁶^ORCID

Affiliation:

1. Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands

2. Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK

3. Current address: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands

4. Technion Integrated Cancer Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel

5. Current address: Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, 1300-477 Lisbon, Portugal

6. The Rosalind Franklin Institute, Harwell, OX11 0FA, UK

Abstract

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.

Funder

EC | ERC | HORIZON EUROPE European Research Council

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Israel Science Foundation

European Molecular Biology Organization

Wellcome Trust

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2203167119