| Literature DB >> 29191878 |
Susan Klaeger1,2,3, Stephanie Heinzlmeir1,2,3, Mathias Wilhelm1, Harald Polzer2,3,4, Binje Vick2,3,5, Paul-Albert Koenig6, Maria Reinecke1,2,3, Benjamin Ruprecht1, Svenja Petzoldt1,2,3, Chen Meng1, Jana Zecha1,2,3, Katrin Reiter2,3,4, Huichao Qiao1, Dominic Helm1, Heiner Koch1,2,3, Melanie Schoof1, Giulia Canevari7, Elena Casale7, Stefania Re Depaolini7, Annette Feuchtinger8, Zhixiang Wu1, Tobias Schmidt1, Lars Rueckert9, Wilhelm Becker9, Jan Huenges9, Anne-Kathrin Garz2,3,10, Bjoern-Oliver Gohlke2,3,11, Daniel Paul Zolg1, Gian Kayser12, Tonu Vooder13,14,15, Robert Preissner2,3,11, Hannes Hahne1, Neeme Tõnisson14,15, Karl Kramer1, Katharina Götze2,3,10, Florian Bassermann2,3,10, Judith Schlegl16, Hans-Christian Ehrlich9, Stephan Aiche9, Axel Walch8, Philipp A Greif2,3,4, Sabine Schneider17,18, Eduard Rudolf Felder7, Juergen Ruland2,3,6, Guillaume Médard1, Irmela Jeremias2,5,19, Karsten Spiekermann2,3,4, Bernhard Kuster20,2,3,18,21.
Abstract
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.Entities:
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Year: 2017 PMID： 29191878 PMCID： PMC6542668 DOI： 10.1126/science.aan4368
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728