دورية أكاديمية
أعرض في EDS

Monitoring drug-target interactions through target engagement-mediated amplification on arrays and in situ.

التفاصيل البيبلوغرافية
العنوان: Monitoring drug-target interactions through target engagement-mediated amplification on arrays and in situ.
المؤلفون: Al-Amin RA; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Johansson L; Department of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet, Solna, Sweden., Abdurakhmanov E; Department of Chemistry-BMC, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Landegren N; Center for Molecular Medicine, Department of Medicine (Solna), Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Löf L; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Arngården L; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Blokzijl A; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Svensson R; Department of Pharmacy, Uppsala University Drug Optimization and Pharmaceutical Profiling (UDOPP), Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Hammond M; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Lönn P; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Haybaeck J; Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria.; Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria., Kamali-Moghaddam M; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Jensen AJ; Department of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet, Solna, Sweden., Danielson UH; Department of Chemistry-BMC, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Artursson P; Department of Pharmacy, Uppsala University Drug Optimization and Pharmaceutical Profiling (UDOPP), Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Lundbäck T; Department of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet, Solna, Sweden., Landegren U; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
المصدر: Nucleic acids research [Nucleic Acids Res] 2022 Dec 09; Vol. 50 (22), pp. e129.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.
مواضيع طبية MeSH: Molecular Targeted Therapy*/methods, Dasatinib/pharmacology ; Oligonucleotide Probes ; Protein Array Analysis ; Proteins ; Gefitinib/pharmacology ; Protein Kinase Inhibitors/pharmacology
مستخلص: 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.
(© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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سلسلة جزيئية: figshare 10.6084/m9.figshare.21107641.v1
المشرفين على المادة: RBZ1571X5H (Dasatinib)
0 (Oligonucleotide Probes)
0 (Proteins)
S65743JHBS (Gefitinib)
0 (Protein Kinase Inhibitors)
تواريخ الأحداث: Date Created: 20221003 Date Completed: 20230111 Latest Revision: 20230127
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9825164
DOI: 10.1093/nar/gkac842
PMID: 36189884
قاعدة البيانات: MEDLINE
الوصف
تدمد:1362-4962
DOI:10.1093/nar/gkac842