Lapatinib 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 entirely understood. Here, we focus on the interaction of these drug molecules with phospholipid membranes, which has not yet been investigated before in molecular detail. Owing to their lipophilic characteristics, quantitatively reflected by large differences of the partition equilibrium between water and octanol phases (expressed by logP values), rather drastic differences in the membrane interaction of both molecules have to be expected. Applying experimental (nuclear magnetic resonance, fluorescence and ESR spectroscopy) and theoretical (molecular dynamics simulations) approaches, we found that lapatinib and tofacitinib bind to lipid membranes and insert into the lipid-water interface of the bilayer. For lapatinib, a deeper embedding into the membrane bilayer was observed than for tofacitinib implying different impacts of the molecules on the bilayer structure. While for tofacitinib, no influence to the membrane structure was found, lapatinib causes a membrane disturbance, as concluded from an increased permeability of the membrane for polar molecules. These data may contribute to a better understanding of the cellular uptake mechanism(s) and the side effects of the drugs.

拉帕替尼和托法替尼是分别批准用于治疗晚期或转移性乳腺癌和类风湿关节炎的小分子激酶抑制剂。到目前为止，尚未完全了解负责其活动的机制。在这里，我们专注于这些药物分子与磷脂膜的相互作用，这尚未在分子细节上进行过研究。由于它们的亲脂特性，在水和辛醇相之间的分配平衡存在较大差异（由logP值表示）时，定量地反映了这一点，因此必须预料到两种分子的膜相互作用都将出现巨大差异。应用实验方法（核磁共振，荧光和ESR光谱）和理论方法（分子动力学模拟），我们发现拉帕替尼和托法替尼与脂质膜结合并插入双层的脂质-水界面。对于拉帕替尼，观察到的嵌入膜双层的深度比对托法替尼更深，这暗示了分子对双层结构的不同影响。对于托法替尼，未发现对膜结构的影响，而拉帕替尼会引起膜紊乱，这是由于膜对极性分子的渗透性增加所得出的结论。这些数据可能有助于更好地了解细胞的摄取机制和药物的副作用。与tofacitinib相比，在膜双层中的嵌入更深，这暗示了分子对双层结构的不同影响。对于托法替尼，未发现对膜结构的影响，而拉帕替尼会引起膜紊乱，这是由于膜对极性分子的渗透性增加所得出的结论。这些数据可能有助于更好地了解细胞的摄取机制和药物的副作用。与tofacitinib相比，观察到了更深层的嵌入膜双层，这暗示了分子对双层结构的不同影响。对于托法替尼，未发现对膜结构的影响，而拉帕替尼会引起膜紊乱，这是由于膜对极性分子的渗透性增加所得出的结论。这些数据可能有助于更好地了解细胞的摄取机制和药物的副作用。