CONICET | Buscador de Institutos y Recursos Humanos

Lapanitib and tofacitinib are small-molecule kinase inhibitors approved for the treatment of advanced or metastatic breast cancer and rheumatoid arthritis, respectively. So far, the mechanisms which are responsible for their activities are not completely understood.Here, we focused on the interaction of these drug molecules with membranes, which has not been investigated so far in detail. Regarding their lipophilic characteristics, quantitatively reflected by large differences of the logP values, different membrane interactions of both molecules have to be expected. Applying experimental (nuclear magnetic resonance, fluorescence and ESR spectroscopy) and theoretical (MDsimulations) approaches, we found that lapanitib and tofacitinib bind to lipid membranes and insert into the lipid-water interface of the membrane. For lapatinib a deeper embedding into the lipid bilayer was observed leading to a different impact of the molecules on the membrane. Whereas, for tofacitinib no influence was found, lapatinibcauses a disturbance of membrane structure, as seen from an increased permeability of the membrane for polar molecules. These data may contribute to a better understanding of the effectiveness of these drugs in the treatment of respective deceases and their side effects.