Interaction of the Small-Molecule Kinase Inhibitors Tofacitinib and Lapatinib with Model Membranes

LUCK, MEIKE; SCHEIDT, HOLGER A.; DI LELLA, SANTIAGO; ALONSO DE ARMIÑO, DIEGO JAVIER; MÜLLER, PETER; HARALAMPIEV, IVAN; HUSTER, DANIEL

Drübeck

Encuentro; International DGfB Membrane Biophysics Meeting - Methods for Membrane Biophysics; 2020

Deutsche Gesellschaft für Biophysik

Lapanitib and tofacitinib are small-molecule kinase inhibitors approved for the treatment of advanced or metastaticbreast cancer and rheumatoid arthritis, respectively. So far, the mechanisms which are responsible for their activities arenot completely understood. Here, we focused on the interaction of these drug molecules with membranes, which has notbeen investigated so far in detail. Regarding their lipophilic characteristics, quantitatively reflected by large differencesof the logP values, different membrane interactions of both molecules have to be expected. Applying experimental(nuclear magnetic resonance, fluorescence and ESR spectroscopy) and theoretical (MD simulations) approaches, wefound 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 onthe membrane. Whereas, for tofacitinib no influence was found, lapatinib causes a disturbance of membrane structure,as seen from an increased permeability of the membrane for polar molecules. These data may contribute to a betterunderstanding of the effectiveness of these drugs in the treatment of respective deceases and their side effects.