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Article: Chemical proteomic profiling of bromodomains enables the wide-spectrum evaluation of bromodomain inhibitors in living cells

TitleChemical proteomic profiling of bromodomains enables the wide-spectrum evaluation of bromodomain inhibitors in living cells
Authors
Issue Date2019
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.html
Citation
Journal of the American Chemical Society, 2019, v. 141 n. 29, p. 11497-11505 How to Cite?
AbstractBromodomains, epigenetic 'readers' of lysine acetylation marks, exist in different nuclear proteins with diverse biological functions in chromatin biology. Malfunctions of bromodomains are associated with the pathogenesis of human diseases, such as cancer. Bromodomains have therefore emerged as therapeutic targets for drug discovery. Given the high structural similarity of bromodomains, a critical step in the development of bromodomain inhibitors is the evaluation of their selectivity to avoid off-target effects. While numerous bromodomain inhibitors have been identified, new methods to evaluate the inhibitor selectivity toward endogenous bromodomains in living cells remain needed. Here we report the development of a photoaffinity probe, photo-bromosporine (photo-BS), that enables the wide-spectrum profiling of bromodomain inhibitors in living cells. Photo-BS allowed light-induced cross-linking of recombinant bromodomains and endogenous bromodomain-containing proteins (BCPs) both in vitro and in living cells. The photo-BS-induced labeling of the bromodomains was selectively competed by the corresponding bromodomain inhibitors. Proteomics analysis revealed that photo-BS captured 28 out of the 42 known BCPs from the living cells. Assessment of the two bromodomain inhibitors, bromosporine and GSK6853, resulted in the identification of known as well as previously uncharacterized bromodomain targets. Collectively, we established a chemical proteomics platform to comprehensively evaluate bromodomain inhibitors in terms of their selectivity against endogenous BCPs in living cells.
Persistent Identifierhttp://hdl.handle.net/10722/272841
ISSN
2017 Impact Factor: 14.357
2015 SCImago Journal Rankings: 7.123

 

DC FieldValueLanguage
dc.contributor.authorLi, X-
dc.contributor.authorWU, Y-
dc.contributor.authorTIAN, G-
dc.contributor.authorJIANG, Y-
dc.contributor.authorLiu, Z-
dc.contributor.authorMeng, X-
dc.contributor.authorBao, X-
dc.contributor.authorFeng, L-
dc.contributor.authorSun, H-
dc.contributor.authorDeng, H-
dc.contributor.authorLi, XD-
dc.date.accessioned2019-08-06T09:17:35Z-
dc.date.available2019-08-06T09:17:35Z-
dc.date.issued2019-
dc.identifier.citationJournal of the American Chemical Society, 2019, v. 141 n. 29, p. 11497-11505-
dc.identifier.issn0002-7863-
dc.identifier.urihttp://hdl.handle.net/10722/272841-
dc.description.abstractBromodomains, epigenetic 'readers' of lysine acetylation marks, exist in different nuclear proteins with diverse biological functions in chromatin biology. Malfunctions of bromodomains are associated with the pathogenesis of human diseases, such as cancer. Bromodomains have therefore emerged as therapeutic targets for drug discovery. Given the high structural similarity of bromodomains, a critical step in the development of bromodomain inhibitors is the evaluation of their selectivity to avoid off-target effects. While numerous bromodomain inhibitors have been identified, new methods to evaluate the inhibitor selectivity toward endogenous bromodomains in living cells remain needed. Here we report the development of a photoaffinity probe, photo-bromosporine (photo-BS), that enables the wide-spectrum profiling of bromodomain inhibitors in living cells. Photo-BS allowed light-induced cross-linking of recombinant bromodomains and endogenous bromodomain-containing proteins (BCPs) both in vitro and in living cells. The photo-BS-induced labeling of the bromodomains was selectively competed by the corresponding bromodomain inhibitors. Proteomics analysis revealed that photo-BS captured 28 out of the 42 known BCPs from the living cells. Assessment of the two bromodomain inhibitors, bromosporine and GSK6853, resulted in the identification of known as well as previously uncharacterized bromodomain targets. Collectively, we established a chemical proteomics platform to comprehensively evaluate bromodomain inhibitors in terms of their selectivity against endogenous BCPs in living cells.-
dc.languageeng-
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.html-
dc.relation.ispartofJournal of the American Chemical Society-
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in [JournalTitle], copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see http://pubs.acs.org/page/policy/articlesonrequest/index.html].-
dc.titleChemical proteomic profiling of bromodomains enables the wide-spectrum evaluation of bromodomain inhibitors in living cells-
dc.typeArticle-
dc.identifier.emailLi, X: lx418@hku.hk-
dc.identifier.emailLiu, Z: lz0418@hku.hk-
dc.identifier.emailBao, X: baoxc@hku.hk-
dc.identifier.emailLi, XD: xiangli@hku.hk-
dc.identifier.authorityLi, XD=rp01562-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/jacs.9b02738-
dc.identifier.pmid31246451-
dc.identifier.scopuseid_2-s2.0-85070485649-
dc.identifier.hkuros300669-
dc.identifier.volume141-
dc.identifier.issue29-
dc.identifier.spage11497-
dc.identifier.epage11505-
dc.publisher.placeUnited States-

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