Portal de Periódicos da CAPES

The target landscape of clinical kinase drugs

2017; American Association for the Advancement of Science; Volume: 358; Issue: 6367 Linguagem: Inglês

10.1126/science.aan4368

1095-9203

Susan Klaeger, Stephanie Heinzlmeir, Mathias Wilhelm, Harald Polzer, Binje Vick, Paul-Albert Koenig, Maria Reinecke, Benjamin Ruprecht, Svenja Wiechmann, Chen Meng, Jana Zecha, Katrin Reiter, Huichao Qiao, Dominic Helm, Heiner Koch, Melanie Schoof, Giulia Canevari, Elena Casale, Stefania Re Depaolini, Annette Feuchtinger, Zhixiang Wu, Tobias Schmidt, Lars Rueckert, Wilhelm Becker, Jan Huenges, Anne-Kathrin Garz, Björn-Oliver Gohlke, Daniel P. Zolg, Gian Kayser, Tõnu Vooder, Robert Preißner, Hannes Hahne, Neeme Tõnisson, Karl Kramer, Katharina S. Götze, Florian Bassermann, Judith Schlegl, Hans‐Christian Ehrlich, Stephan Aiche, Axel Walch, Philipp A. Greif, Sabine Schneider, Eduard Felder, Jürgen Ruland, Guillaume Médard, Irmela Jeremias, Karsten Spiekermann, Bernhard Küster,

PI3K/AKT/mTOR signaling in cancer

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.