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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| Format: | Article |
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MDPI AG
2021-11-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/11/1131 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:10:09Z |
| format | Article |
| id | doaj.art-95c424c0932d4672ab5e9ae929d2cd2a |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T05:10:09Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-95c424c0932d4672ab5e9ae929d2cd2a2023-11-23T00:55:42ZengMDPI AGPharmaceuticals1424-82472021-11-011411113110.3390/ph14111131Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of ChalconesMarta Gargantilla0José López-Fernández1Maria-Jose Camarasa2Leentje Persoons3Dirk Daelemans4Eva-Maria Priego5María-Jesús Pérez-Pérez6Instituto de Química Médica (IQM, CSIC) c/Juan de la Cierva 3, 28006 Madrid, SpainInstituto de Química Médica (IQM, CSIC) c/Juan de la Cierva 3, 28006 Madrid, SpainInstituto de Química Médica (IQM, CSIC) c/Juan de la Cierva 3, 28006 Madrid, SpainKU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumKU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumInstituto de Química Médica (IQM, CSIC) c/Juan de la Cierva 3, 28006 Madrid, SpainInstituto de Química Médica (IQM, CSIC) c/Juan de la Cierva 3, 28006 Madrid, SpainThe 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.https://www.mdpi.com/1424-8247/14/11/1131chalconesexportin-1covalent bindingCovDockanticancer activity |
| spellingShingle | 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 Pharmaceuticals chalcones exportin-1 covalent binding CovDock anticancer activity |
| title | 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_short | 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 |
| topic | chalcones exportin-1 covalent binding CovDock anticancer activity |
| url | https://www.mdpi.com/1424-8247/14/11/1131 |
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