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 principales:	Marta Gargantilla, José López-Fernández, Maria-Jose Camarasa, Leentje Persoons, Dirk Daelemans, Eva-Maria Priego, María-Jesús Pérez-Pérez
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	chalcones exportin-1 covalent binding CovDock anticancer activity Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/95c424c0932d4672ab5e9ae929d2cd2a
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spelling	oai:doaj.org-article:95c424c0932d4672ab5e9ae929d2cd2a2021-11-25T18:39:35ZInhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones10.3390/ph141111311424-8247https://doaj.org/article/95c424c0932d4672ab5e9ae929d2cd2a2021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1131https://doaj.org/toc/1424-8247The 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 <b>9</b> and <b>10</b> 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 CovDock.Marta GargantillaJosé López-FernándezMaria-Jose CamarasaLeentje PersoonsDirk DaelemansEva-Maria PriegoMaría-Jesús Pérez-PérezMDPI AGarticlechalconesexportin-1covalent bindingCovDockanticancer activityMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1131, p 1131 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chalcones exportin-1 covalent binding CovDock anticancer activity Medicine R Pharmacy and materia medica RS1-441
spellingShingle	chalcones exportin-1 covalent binding CovDock anticancer activity Medicine R Pharmacy and materia medica RS1-441 Marta Gargantilla José López-Fernández Maria-Jose Camarasa Leentje Persoons Dirk Daelemans Eva-Maria Priego María-Jesús Pérez-Pérez Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
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 <b>9</b> and <b>10</b> 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 CovDock.
format	article
author	Marta Gargantilla José López-Fernández Maria-Jose Camarasa Leentje Persoons Dirk Daelemans Eva-Maria Priego María-Jesús Pérez-Pérez
author_facet	Marta Gargantilla José López-Fernández Maria-Jose Camarasa Leentje Persoons Dirk Daelemans Eva-Maria Priego María-Jesús Pérez-Pérez
author_sort	Marta Gargantilla
title	Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones
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
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/95c424c0932d4672ab5e9ae929d2cd2a
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Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones

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