Chemical proteomics reveals target selectivity of clinical Jak inhibitors in human primary cells
| العنوان: | Chemical proteomics reveals target selectivity of clinical Jak inhibitors in human primary cells |
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| المؤلفون: | Thilo Werner, Christina Rau, Marcus Bantscheff, David H. Drewry, Stephanie Lehmann, H. Christian Eberl, Peiling Chen, Gerard Drewes, Marcel Muelbaier, Friedrich B M Reinhard, Douglas W. Thomson, Cunyu Zhang |
| المصدر: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019) |
| بيانات النشر: | Nature Publishing Group UK, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Proteomics, Proteome, Dasatinib, lcsh:Medicine, Kinases, Plasma protein binding, Article, Chromatography, Affinity, Monocytes, Substrate Specificity, Sepharose, 03 medical and health sciences, Mice, 0302 clinical medicine, Dogs, Target identification, medicine, Animals, Humans, Kinome, Chemoproteomics, lcsh:Science, Protein Kinase Inhibitors, Janus Kinases, Multidisciplinary, Chemistry, Kinase, lcsh:R, Microspheres, 030104 developmental biology, HEK293 Cells, Biochemistry, 030220 oncology & carcinogenesis, lcsh:Q, Janus kinase, K562 Cells, medicine.drug, Protein Binding |
| الوصف: | Kinobeads are a set of promiscuous kinase inhibitors immobilized on sepharose beads for the comprehensive enrichment of endogenously expressed protein kinases from cell lines and tissues. These beads enable chemoproteomics profiling of kinase inhibitors of interest in dose-dependent competition studies in combination with quantitative mass spectrometry. We present improved bead matrices that capture more than 350 protein kinases and 15 lipid kinases from human cell lysates, respectively. A multiplexing strategy is suggested that enables determination of apparent dissociation constants in a single mass spectrometry experiment. Miniaturization of the procedure enabled determining the target selectivity of the clinical BCR-ABL inhibitor dasatinib in peripheral blood mononuclear cell (PBMC) lysates from individual donors. Profiling of a set of Jak kinase inhibitors revealed kinase off-targets from nearly all kinase families underpinning the need to profile kinase inhibitors against the kinome. Potently bound off-targets of clinical inhibitors suggest polypharmacology, e.g. through MRCK alpha and beta, which bind to decernotinib with nanomolar affinity. |
| اللغة: | English |
| تدمد: | 2045-2322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e6a9de49167af020ba0934799448773c http://europepmc.org/articles/PMC6775116 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e6a9de49167af020ba0934799448773c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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