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http://hdl.handle.net/10261/186404
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Campo DC | Valor | Lengua/Idioma |
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dc.contributor.author | Quintana, Mireia | es_ES |
dc.contributor.author | Bilbao, Ana | es_ES |
dc.contributor.author | Comas-Barceló, Júlia | es_ES |
dc.contributor.author | Bujons, Jordi | es_ES |
dc.contributor.author | Triola Guillem, Gemma | es_ES |
dc.date.accessioned | 2019-07-19T08:37:17Z | - |
dc.date.available | 2019-07-19T08:37:17Z | - |
dc.date.issued | 2019-09-15 | - |
dc.identifier.citation | European Journal of Medicinal Chemistry | es_ES |
dc.identifier.uri | http://hdl.handle.net/10261/186404 | - |
dc.description.abstract | Targeting autophagy is a promising therapeutic strategy for cancer treatment. As a result, the identification of novel autophagy inhibitors is an emerging field of research. Herein, we report the development of a novel AlphaScreen HTS assay that combined with a MS-based assay and a structure-based high-throughput virtual screening have enabled the identification of benzo[cd]indol-2(1H)-one as a novel scaffold that targets Atg4B. Thus, an initial screening campaign led to the identification of NSC126353 and NSC611216 bearing a chlorohydrin moiety. Structural-activity relationship analysis of the initial hits provided an optimized lead, compound 33, bearing a 7-aminobenzo[cd]indol-2-[1H]-one scaffold and a propyl group replacing the chlorine. Inhibition of autophagy was also investigated in cells by measuring LC3-II and p62 protein levels. Moreover, the synergistic effect of 33 combined with oxaliplatin resulted in an enhanced cell death in the human colorectal adenocarcinoma cell line HT-29. We are convinced that the developed AlphaScreen and MS-based assays can be key tools enabling the high-throughput identification of novel Atg4B inhibitors. Moreover, the aminobenzo[cd]indol-2-[1H]-one scaffold represents a novel chemotype for the further development of small molecule inhibitors of Atg4B. © 2019 Elsevier Masson SAS | es_ES |
dc.description.sponsorship | We would like to thank Karel Hernandez and Roman Bonet for his support in the expression and purification of recombinant proteins and Kristina Lang for her help in the preparation of N-(His) 6 -LC3B-L123C. We are grateful to the Ministerio de Economia and Competitividad for supporting this work with a research grant CTQ2013-44334-P ) and FPI fellowship to A.B.G ( BES-2014-070026 ). Appendix A | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2013-44334-P | es_ES |
dc.relation.isversionof | Postprint | es_ES |
dc.rights | openAccess | en_EN |
dc.subject | LC3 | es_ES |
dc.subject | AlphaScreen | es_ES |
dc.subject | Autophagy | es_ES |
dc.subject | Atg4B | es_ES |
dc.title | Identification of benzo[cd]indol-2(1H)-ones as novel Atg4B inhibitors via a structure-based virtual screening and a novel AlphaScreen assay | es_ES |
dc.type | artículo | es_ES |
dc.identifier.doi | 10.1016/j.ejmech.2019.05.086 | - |
dc.description.peerreviewed | Peer reviewed | es_ES |
dc.relation.publisherversion | https://doi.org/10.1016/j.ejmech.2019.05.086 | es_ES |
dc.embargo.terms | 2021-09-15 | es_ES |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | es_ES |
dc.relation.csic | Sí | es_ES |
oprm.item.hasRevision | no ko 0 false | * |
dc.identifier.funder | http://dx.doi.org/10.13039/501100003329 | es_ES |
dc.contributor.orcid | Bujons, Jordi [0000-0003-2944-2905] | es_ES |
dc.contributor.orcid | Triola, Gemma [0000-0003-4177-8989] | es_ES |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.openairetype | artículo | - |
item.grantfulltext | open | - |
item.cerifentitytype | Publications | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | With Fulltext | - |
item.languageiso639-1 | en | - |
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Identification of benzo[cd]indol-2(1H)-ones as novel Atg4B inhibitors via a structure-based virtual screening and a novel AlphaScreen assay.pdf | Artículo principal | 6,81 MB | Adobe PDF | Visualizar/Abrir |
Identification of benzo[cd]indol-2(1H)-ones as novel Atg4B inhibitors via a structure-based virtual screening and a novel AlphaScreen assay.Figures.pdf | Material suplementario | 22,23 MB | Adobe PDF | Visualizar/Abrir |
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