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• W2782458693 abstract "Protein kinases are key signaling molecules in the cell and catalyze the phosphate group transfer of ATP to their respective substrates. They have emerged as major drug target class, as they are often aberrant in diseases like cancer or inflammation. Small molecule kinase inhibitors provide one treatment option. Over 250 of these molecules are currently evaluated in clinical trials; over 30 have already been approved for human therapy. Most of them mimic ATP, thus targeting the ATP-binding pocket of kinases and preventing signal transduction via phosphate-transfer. As the ATP-binding pocket is quite conserved across the 518 protein kinases, many inhibitors can bind to more than one target protein. This polypharmacology can be advantageous and lead to the use of one drug in more than one indication. It might also lead to side effects and has influence on the mode of action of a drug. Therefore, thorough evaluation of the target space of a kinase inhibitor and its selectivity is necessary.In this study, 242 small molecule inhibitors currently tested in clinical trials have been subjected to competitive Kinobeads profiling in a dose dependent manner followed by LC-MS/MS readout. The Kinobeads technology allows enrichment of over 300 kinases from cell or tissue lysate by binding of the ATP pocket. Competition with a free inhibitor for the ATP pocket leads to a dose dependent decrease of potential targets on the beads. Thus, drug-protein interaction profiles for each drug and all proteins bound by Kinobeads can be obtained. These allow determination of effective concentrations for half-maximal inhibition EC50 values and apparent binding constants. The selectivity of the investigated panel ranges from very selective drugs to unselective, multi-kinase inhibitors. Selective inhibition is desirable for unambiguous drug-protein interaction studies in basic research and thus, these inhibitors might be directly used as chemical probes, whereas more unselective inhibitors might be beneficial for the therapeutic success of a drug. Kinase inhibitor selectivity can be influenced by a number of factors. No major difference between inhibitors targeting the ‘DFG-in’ confirmation of kinases (type 1) and those binding the ‘DFG-out’ confirmation (type 2) inhibitors could be observed, whereas the allosteric (type 3) inhibitors could be confirmed as selective MAP2K1 and MAP2K2 drugs. Irreversible EGFR inhibitors were not necessarily more selective than their reversible counterparts. Reversible inhibitors can have no further additional targets; irreversible inhibitors are often more affine for EGFR than their off-targets. The observed additional off-targets of some drugs can explain adverse effects or generate rational hypotheses for drug repositioning. This work raises many opportunities for both cases. A set of six inhibitors was examined further for their additional NTRK1 inhibition in colon cancer and the approved MET-inhibitor Cabozantinib was evaluated in FLT3-ITD driven acute myeloid leukemia. Another important finding was the non-kinase off-target Ferrochelatase for 12% of all inhibitors. The protoporphyrin pocket of this enzyme could be determined as the binding site for some of these inhibitors and inhibition is likely linked to the side effect of photosensitivity in some patients receiving these inhibitors, as observed in Vemurafenib therapy. To conclude, this work revealed the target landscape of small molecule inhibitors with the use of chemical proteomics. This thesis offers new insights into inhibitor selectivity and the druggable kinome. It can help to understand the molecular mode of actions of inhibitors and molecular reasons for side effects. Furthermore, new possibilities for drug repurposing as well as inhibitor design can be generated. It can be anticipated that this study will have impact on multiple disciplines like basic research, medicinal chemistry, cell biology, and medicine." @default.
• W2782458693 created "2018-01-12" @default.
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• W2782458693 date "2017-01-01" @default.
• W2782458693 modified "2023-09-26" @default.
• W2782458693 title "Chemical Proteomics Reveals the Target Landscape of Clinical Kinase Inhibitors." @default.
• W2782458693 hasPublicationYear "2017" @default.
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