The target landscape of clinical kinase drugs

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 previousl...

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Published in:Science (American Association for the Advancement of Science) 2017-12, Vol.358 (6367), p.1148-1148
Main Authors: Klaeger, Susan, Heinzlmeir, Stephanie, Wilhelm, Mathias, Polzer, Harald, Vick, Binje, Koenig, Paul-Albert, Reinecke, Maria, Ruprecht, Benjamin, Petzoldt, Svenja, Meng, Chen, Zecha, Jana, Reiter, Katrin, Qiao, Huichao, Helm, Dominic, Koch, Heiner, Schoof, Melanie, Canevari, Giulia, Casale, Elena, Re Depaolini, Stefania, Feuchtinger, Annette, Wu, Zhixiang, Schmidt, Tobias, Rueckert, Lars, Becker, Wilhelm, Huenges, Jan, Garz, Anne-Kathrin, Gohlke, Bjoern-Oliver, Zolg, Daniel Paul, Kayser, Gian, Vooder, Tonu, Preissner, Robert, Hahne, Hannes, Tõnisson, Neeme, Kramer, Karl, Götze, Katharina, Bassermann, Florian, Schlegl, Judith, Ehrlich, Hans-Christian, Aiche, Stephan, Walch, Axel, Greif, Philipp A., Schneider, Sabine, Felder, Eduard Rudolf, Ruland, Juergen, Médard, Guillaume, Jeremias, Irmela, Spiekermann, Karsten, Kuster, Bernhard
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Affinity
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological effects
Biomolecules
Bruton's tyrosine kinase
Cancer
Cancer therapies
Cell Line, Tumor
Clinical trials
Cytokines - metabolism
Data processing
Decision making
Deregulation
Drug development
Drug discovery
Drug Discovery - methods
Drugs
Embryos
Epidermal growth factor
Epidermal growth factor receptors
fms-Like Tyrosine Kinase 3 - antagonists & inhibitors
Humans
Imatinib
Inflammatory diseases
Inhibitors
Interleukin 10
Kinases
Lead compounds
Leucine
Leucine zipper proteins
Leukemia
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - enzymology
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - enzymology
Markers
Mass spectrometry
Mass spectroscopy
Medical research
Medical treatment
Mice
Mode of action
Molecular Targeted Therapy
Myeloid leukemia
Narcotics
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein Serine-Threonine Kinases - antagonists & inhibitors
Protein-tyrosine kinase
Proteomics
Proteomics - methods
R&D
Research & development
RESEARCH ARTICLE SUMMARY
Salt-inducible kinase
Salts
Selectivity
Side effects
Signal transduction
Signaling
Target recognition
Therapeutic applications
Tumor necrosis factor-α
Tyrosine
Xenograft Model Antitumor Assays
Xenografts
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aan4368