Characterizing the Interaction of Small-Molecule Kinase Inhibitors with Membranes to Understand their Specific Cellular Effects

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Protein kinases are one of the biologically most important protein families which play a significant role in the regulation of nearly all physiological processes since they modulate the function of proteins. Due to this unique importance, mutation(s) or dysregulation(s) of protein kinases are a cause of many human diseases. Therefore, members of this family of enzymes have become very important drug targets over the past two decades. One strategy to treat diseases was to develop and apply kinase inhibitors (small molecule protein kinase inhibitors), which are mainly applied in cancer therapy. For most of these drugs, clinical data and structure-activity relationships have been reported and cellular mechanisms have been proposed to explain their antitumor activity. However, the current knowledge about the interaction and impact of these drugs with/on membranes especially with regard to the role of membrane lipids is insufficient. This is surprising since (i) (plasma) membranes are the first target of interaction and (ii) an impact of the drugs on the target kinase and/or off-targets can be assumed to be modulated by membranes. Therefore, the project aims to characterize the interaction of selected small-molecule kinase inhibitors with lipid membranes. Drugs will be selected on the basis of different chemical structures suggesting a different pattern of membrane interactions. Experiments are planned to provide qualitative and quantitative data on lipid vesicles and on cells using different biophysical approaches. The influence of the drug molecules on structural and dynamical membrane properties as well as their membrane position and orientation will be investigated in different lipid membrane compositions. Experiments on cells will show how the results on model membranes can be translated into the physiological system. Molecular dynamics simulations shall provide further insights of the drug impact on an atomistic level. The experiments will highlight the role of membrane lipids for the impact of small-molecule kinase inhibitors. We expect that the results will (i) allow to set up molecular models of drug-membrane interaction, (ii) give the basis for proposing modifications of the molecule structure in order to improve drug impact, and (iii) contribute to a better understanding of the cellular effects of these molecules with regard to their efficacy but also to their side effects and interactions with off-targets.