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Klaeger, S.* ; Heinzlmeir, S.* ; Wilhelm, M.* ; Polzer, H.* ; Vick, B. ; Koenig, P.A.* ; Reinecke, M.* ; Ruprecht, B.* ; Petzoldt, S.* ; Meng, C.* ; Zecha, J.* ; Reiter, K.* ; Qiao, H.* ; Helm, D.* ; Koch, H.* ; Schoof, M.* ; Canevari, G.* ; Casale, E.* ; Depaolini, S.R.* ; Feuchtinger, A. ; Wu, Z.* ; Schmidt, T.* ; Rueckert, L.* ; Becker, W.* ; Huenges, J.* ; Garz, A.K.* ; Gohlke, B.O.* ; Zolg, D.P.* ; Kayser, G.* ; Vooder, T.* ; Preissner, R.* ; Hahne, H.* ; Tõnisson, N.* ; Kramer, K.* ; Götze, K.* ; Bassermann, F.* ; Schlegl, J.* ; Ehrlich, H.C.* ; Aiche, S.* ; Walch, A.K. ; Greif, P.A.* ; Schneider, S.* ; Felder, E.R.* ; Ruland, J.* ; Médard, G.* ; Jeremias, I. ; Spiekermann, K.* ; Kuster, B.*

The target landscape of clinical kinase drugs.

Science 358:eaan4368 (2017)
Publ. Version/Full Text Postprint DOI PMC
Open Access Green
Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Integrative Genomics Viewer; Salt-inducible Kinases; Chemical Proteomics; Inhibitor Selectivity; Comprehensive Analysis; Data Quality; Protein; Quantification; Refinement; Cancer
ISSN (print) / ISBN 0036-8075
e-ISSN 1095-9203
Journal Science
Quellenangaben Volume: 358, Issue: 6367, Pages: , Article Number: eaan4368 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoetic Stem Cells (AHS)
Core Facilty Pathology and Tissue Analytics (CF-PTA)
Research Unit Analytical Pathology (AAP)