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dc.contributor.authorQuintana, Mireiaes_ES
dc.contributor.authorBilbao, Anaes_ES
dc.contributor.authorComas-Barceló, Júliaes_ES
dc.contributor.authorBujons, Jordies_ES
dc.contributor.authorTriola, Gemmaes_ES
dc.date.accessioned2019-07-19T08:37:17Z-
dc.date.available2019-07-19T08:37:17Z-
dc.date.issued2019-09-15-
dc.identifier.citationEuropean Journal of Medicinal Chemistryes_ES
dc.identifier.urihttp://hdl.handle.net/10261/186404-
dc.description.abstractTargeting 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 SASes_ES
dc.description.sponsorshipWe 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 Aes_ES
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.relationMINECO/ICTI2013-2016/CTQ2013-44334-Pes_ES
dc.relation.isversionofPostprintes_ES
dc.rightsembargoedAccesses_ES
dc.subjectLC3es_ES
dc.subjectAlphaScreenes_ES
dc.subjectAutophagyes_ES
dc.subjectAtg4Bes_ES
dc.titleIdentification of benzo[cd]indol-2(1H)-ones as novel Atg4B inhibitors via a structure-based virtual screening and a novel AlphaScreen assayes_ES
dc.typeartículoes_ES
dc.identifier.doi10.1016/j.ejmech.2019.05.086-
dc.description.peerreviewedPeer reviewedes_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.ejmech.2019.05.086es_ES
dc.embargo.terms2021-09-15es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.relation.csices_ES
oprm.item.hasRevisionno ko 0 false*
dc.identifier.funderhttp://dx.doi.org/10.13039/501100003329es_ES
dc.contributor.orcidBujons, Jordi [0000-0003-2944-2905]es_ES
dc.contributor.orcidTriola, Gemma [0000-0003-4177-8989]es_ES
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