Borlandelli, Valentina, Armstrong, Zachary, Nin-Hill, Alba et al. (6 more authors) (2023) 4-O-Substituted Glucuronic Cyclophellitols are Selective Mechanism-Based Heparanase Inhibitors. ChemMedChem. e202200580. ISSN 1860-7187
Abstract
Degradation of the extracellular matrix (ECM) supports tissue integrity and homeostasis, but is also a key factor in cancer metastasis. Heparanase (HPSE) is a mammalian ECM-remodeling enzyme with β-D-endo-glucuronidase activity overexpressed in several malignancies, and is thought to facilitate tumor growth and metastasis. By this virtue, HPSE is considered an attractive target for the development of cancer therapies, yet to date no HPSE inhibitors have progressed to the clinic. Here we report on the discovery of glucurono-configured cyclitol derivatives featuring simple substituents at the 4-O-position as irreversible HPSE inhibitors. We show that these compounds, unlike glucurono-cyclophellitol, are selective for HPSE over β-D-exo-glucuronidase (GUSB), also in platelet lysate. The observed selectivity is induced by steric and electrostatic interactions of the substituents at the 4-O-position. Crystallographic analysis supports this rationale for HPSE selectivity, and computer simulations provide insights in the conformational preferences and binding poses of the inhibitors, which we believe are good starting points for the future development of HPSE-targeting antimetastatic cancer drugs.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Funding Information: The authors are grateful for funding from the European Research Council (ERC‐2020‐SyG‐951231 Carbocentre, to C. R., G. J. D. and H. S. O.) and the EU‐Horizon 2020‐Marie Curie Action (ITN814102 Sweet Crosstalk, to H. S. O.), the Spanish Ministry of Science, Innovation and Universities (MICINN/AEI/FEDER, UE, PID2020‐118893GB‐100, to C. R.) and the Spanish Structures of Excellence María de Maeztu (MDM‐2017‐0767, to C. R.). G. J. D. is funded by the Royal Society Ken Murray research Professorship. Z. A. was funded in York on BBSRC grant BB/R001162/1. We thank Diamond Light Source for access to beamline I03 (proposal mx24948), which contributed to the results presented here. C. R. and A. N. H. would like to acknowledge the technical support provided by the Barcelona Supercomputing Center (BSC) and Red Nacional de Supercomputación (RES) for computer resources at MareNostrum IV. Publisher Copyright: © 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH. |
Keywords: | carbohydrates,cyclitols,inhibitors |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Funding Information: | Funder Grant number EUROPEAN COMMISSION 951231 BBSRC (BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL) BB/R001162/1 THE ROYAL SOCIETY RSRP\R\210004 |
Depositing User: | Pure (York) |
Date Deposited: | 22 Feb 2023 11:20 |
Last Modified: | 22 Oct 2024 00:07 |
Published Version: | https://doi.org/10.1002/cmdc.202200580 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1002/cmdc.202200580 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:196695 |
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Description: ChemMedChem - 2022 - Borlandelli - 4‐O‐Substituted Glucuronic Cyclophellitols are Selective Mechanism‐Based Heparanase
Licence: CC-BY-NC-ND 2.5