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Monitoring drug–tar...
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Al-Amin, Rasel A.,Researcher,1983-Uppsala universitet,Molekylära verktyg,Science for Life Laboratory, SciLifeLab
(author)
Monitoring drug–target interactions through target engagement-mediated amplification on arrays and in situ
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2022-10-03
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Oxford University Press,2022
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-461438
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-461438URI
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https://doi.org/10.1093/nar/gkac842DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:150805658URI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Drugs are designed to bind their target proteins in physiologically relevant tissues and organs to modulate biological functions and elicit desirable clinical outcomes. Information about target engagement at cellular and subcellular resolution is therefore critical for guiding compound optimization in drug discovery, and for probing resistance mechanisms to targeted therapies in clinical samples. We describe a target engagement-mediated amplification (TEMA) technology, where oligonucleotide-conjugated drugs are used to visualize and measure target engagement in situ, amplified via rolling-circle replication of circularized oligonucleotide probes. We illustrate the TEMA technique using dasatinib and gefitinib, two kinase inhibitors with distinct selectivity profiles. In vitro binding by the dasatinib probe to arrays of displayed proteins accurately reproduced known selectivity profiles, while their differential binding to fixed adherent cells agreed with expectations from expression profiles of the cells. We also introduce a proximity ligation variant of TEMA to selectively investigate binding to specific target proteins of interest. This form of the assay serves to improve resolution of binding to on- and off-target proteins. In conclusion, TEMA has the potential to aid in drug development and clinical routine by conferring valuable insights in drug–target interactions at spatial resolution in protein arrays, cells and in tissues.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Johansson, LarsDepartment of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet
(author)
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Abdurakhmanov, Eldar,1977-Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab(Swepub:uu)eldab338
(author)
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Landegren, Nils,1986-Karolinska Institutet,Uppsala universitet,Klinisk diabetologi och metabolism,Center for Molecular Medicine, Department of Medicine (Solna), Science for Life Laboratory, Karolinska Institutet(Swepub:uu)nillan544
(author)
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Löf, LizaUppsala universitet,Molekylära verktyg,Science for Life Laboratory, SciLifeLab(Swepub:uu)lizlo931
(author)
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Arngården, Linda,1984-Uppsala universitet,Hematologi(Swepub:uu)linan615
(author)
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Blokzijl, AndriesUppsala universitet,Molekylära verktyg,Science for Life Laboratory, SciLifeLab(Swepub:uu)andbl969
(author)
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Svensson, RichardUppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab(Swepub:uu)ricsv977
(author)
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Hammond, Maria,1984-Uppsala universitet,Molekylära verktyg,Science for Life Laboratory, SciLifeLab(Swepub:uu)marha169
(author)
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Lönn, PeterUppsala universitet,Science for Life Laboratory, SciLifeLab,Molekylära verktyg(Swepub:uu)pelon623
(author)
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Haybaeck, JohannesInstitute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck; Diagnostic and Research Institute of Pathology, Medical University of Graz
(author)
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Kamali-Moghaddam, MasoodUppsala universitet,Molekylära verktyg,Science for Life Laboratory, SciLifeLab(Swepub:uu)masookam
(author)
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Jenmalm Jensen, AnnikaKarolinska Institutet
(author)
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Danielson, U. Helena,Professor,1959-Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab(Swepub:uu)helenads
(author)
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Artursson, PerUppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab(Swepub:uu)perartur
(author)
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Lundbäck, ThomasDepartment of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet
(author)
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Landegren, UlfUppsala universitet,Molekylära verktyg,Science for Life Laboratory, SciLifeLab(Swepub:uu)ulfland
(author)
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Uppsala universitetMolekylära verktyg
(creator_code:org_t)
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In:Nucleic Acids Research: Oxford University Press50:22, s. e129-e1290305-10481362-4962
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