Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones

The nuclear export receptor exportin-1 (XPO1, CRM1) mediates the nuclear export of proteins that contain a leucine-rich nuclear export signal (NES) towards the cytoplasm. XPO1 is considered a relevant target in different human diseases, particularly in hematological malignancies, tumor resistance, i...

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Autores: Gargantilla, Marta, López-Fernández, José, Camarasa Rius, María José, Persoons, Leentje, Daelemans, Dirk, Priego, Eva María, Peréz-Pérez, María-Jesús
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/255421
Acceso en línea:http://hdl.handle.net/10261/255421
Access Level:acceso abierto
Palabra clave:chalcones
exportin-1
covalent binding
CovDock
anticancer activity
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oai_identifier_str oai:digital.csic.es:10261/255421
network_acronym_str ES
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repository_id_str
spelling Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of ChalconesGargantilla, MartaLópez-Fernández, JoséCamarasa Rius, María JoséPersoons, LeentjeDaelemans, DirkPriego, Eva MaríaPeréz-Pérez, María-Jesúschalconesexportin-1covalent bindingCovDockanticancer activityThe nuclear export receptor exportin-1 (XPO1, CRM1) mediates the nuclear export of proteins that contain a leucine-rich nuclear export signal (NES) towards the cytoplasm. XPO1 is considered a relevant target in different human diseases, particularly in hematological malignancies, tumor resistance, inflammation, neurodegeneration and viral infections. Thus, its pharmacological inhibition is of significant therapeutic interest. The best inhibitors described so far (leptomycin B and SINE compounds) interact with XPO1 through a covalent interaction with Cys528 located in the NES-binding cleft of XPO1. Based on the well-established feature of chalcone derivatives to react with thiol groups via hetero-Michael addition reactions, we have synthesized two series of chalcones. Their capacity to react with thiol groups was tested by incubation with GSH to afford the hetero-Michael adducts that evolved backwards to the initial chalcone through a retro-Michael reaction, supporting that the covalent interaction with thiols could be reversible. The chalcone derivatives were evaluated in antiproliferative assays against a panel of cancer cell lines and as XPO1 inhibitors, and a good correlation was observed with the results obtained in both assays. Moreover, no inhibition of the cargo export was observed when the two prototype chalcones 9 and 10 were tested against a XPO1-mutated Jurkat cell line (XPO1C528S), highlighting the importance of the Cys at the NES-binding cleft for inhibition. Finally, their interaction at the molecular level at the NES-binding cleft was studied by applying the computational tool CovDoc.This research was funded by AECSIC, grant number PIE-201980E100 and by Agencia Estatal de Investigación (PID2019-105117RR-C22/ AEI / 10.13039/501100011033 and PID2019- 104070RB-C21).Peer reviewedMultidisciplinary Digital Publishing InstituteAgencia Estatal de Investigación (España)Gargantilla, MartaLópez-Fernández, JoséCamarasa, Maria-José [0000-0002-4978-6468]Priego, Eva-Maria [0000-0001-9470-4508]Peréz-Pérez, María-Jesús [0000-0003-1336-7760]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202120212021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/255421reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.3390/ph14111131Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2554212026-05-22T06:33:51Z
dc.title.none.fl_str_mv Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
title Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
spellingShingle Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
Gargantilla, Marta
chalcones
exportin-1
covalent binding
CovDock
anticancer activity
title_short Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
title_full Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
title_fullStr Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
title_full_unstemmed Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
title_sort Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
dc.creator.none.fl_str_mv Gargantilla, Marta
López-Fernández, José
Camarasa Rius, María José
Persoons, Leentje
Daelemans, Dirk
Priego, Eva María
Peréz-Pérez, María-Jesús
author Gargantilla, Marta
author_facet Gargantilla, Marta
López-Fernández, José
Camarasa Rius, María José
Persoons, Leentje
Daelemans, Dirk
Priego, Eva María
Peréz-Pérez, María-Jesús
author_role author
author2 López-Fernández, José
Camarasa Rius, María José
Persoons, Leentje
Daelemans, Dirk
Priego, Eva María
Peréz-Pérez, María-Jesús
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Agencia Estatal de Investigación (España)
Gargantilla, Marta
López-Fernández, José
Camarasa, Maria-José [0000-0002-4978-6468]
Priego, Eva-Maria [0000-0001-9470-4508]
Peréz-Pérez, María-Jesús [0000-0003-1336-7760]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv chalcones
exportin-1
covalent binding
CovDock
anticancer activity
topic chalcones
exportin-1
covalent binding
CovDock
anticancer activity
description The nuclear export receptor exportin-1 (XPO1, CRM1) mediates the nuclear export of proteins that contain a leucine-rich nuclear export signal (NES) towards the cytoplasm. XPO1 is considered a relevant target in different human diseases, particularly in hematological malignancies, tumor resistance, inflammation, neurodegeneration and viral infections. Thus, its pharmacological inhibition is of significant therapeutic interest. The best inhibitors described so far (leptomycin B and SINE compounds) interact with XPO1 through a covalent interaction with Cys528 located in the NES-binding cleft of XPO1. Based on the well-established feature of chalcone derivatives to react with thiol groups via hetero-Michael addition reactions, we have synthesized two series of chalcones. Their capacity to react with thiol groups was tested by incubation with GSH to afford the hetero-Michael adducts that evolved backwards to the initial chalcone through a retro-Michael reaction, supporting that the covalent interaction with thiols could be reversible. The chalcone derivatives were evaluated in antiproliferative assays against a panel of cancer cell lines and as XPO1 inhibitors, and a good correlation was observed with the results obtained in both assays. Moreover, no inhibition of the cargo export was observed when the two prototype chalcones 9 and 10 were tested against a XPO1-mutated Jurkat cell line (XPO1C528S), highlighting the importance of the Cys at the NES-binding cleft for inhibition. Finally, their interaction at the molecular level at the NES-binding cleft was studied by applying the computational tool CovDoc.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/255421
url http://hdl.handle.net/10261/255421
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.3390/ph14111131
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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