The small-molecule kinase inhibitor ceritinib, unlike imatinib, causes a significant disturbance of lipid membrane integrity: A combined experimental and MD study

IF 3.4 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Chemistry and Physics of Lipids Pub Date : 2023-11-01 DOI:10.1016/j.chemphyslip.2023.105351

Markus Fischer , Meike Luck , Max Werle , Alexander Vogel , Mohammad Bashawat , Kai Ludwig , Holger A. Scheidt , Peter Müller

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Abstract

Ceritinib and imatinib are small-molecule protein kinase inhibitors which are applied as therapeutic agents against various diseases. The fundamentals of their clinical use, i.e. their pharmacokinetics as well as the mechanisms of the inhibition of the respective kinases, are relatively well studied. However, the interaction of the drugs with membranes, which can be a possible cause of side effects, has hardly been investigated so far. Therefore, we have characterized the interaction of both drugs with lipid membranes consisting of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) in the absence and in the presence of cholesterol. For determining the membrane impact of both drugs on a molecular level, different experimental (NMR, ESR, fluorescence) and theoretical (MD simulations) approaches were applied. The data show that ceritinib, in contrast to imatinib, interacts more effectively with membranes significantly affecting various physico-chemical membrane parameters like membrane order and transmembrane permeation of polar solutes. The pronounced membrane impact of ceritinib can be explained by a strong affinity of the drug towards POPC which competes with the POPC-cholesterol interaction by that attenuating the ordering effect of cholesterol. The data are relevant for understanding putative toxic and cytotoxic side effects of these drugs such as the triggering of cell lysis or apoptosis.

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与伊马替尼不同，小分子激酶抑制剂西替尼会对脂质膜完整性造成显著干扰：一项实验和MD联合研究。

赛替尼和伊马替尼是小分子蛋白激酶抑制剂，用作治疗各种疾病的药物。它们临床应用的基本原理，即它们的药代动力学以及各自激酶的抑制机制，都得到了相对良好的研究。然而，到目前为止，药物与膜的相互作用几乎没有得到研究，这可能是副作用的一个原因。因此，我们已经表征了两种药物在不存在和存在胆固醇的情况下与由1-棕榈酰-2-油酰基-sn-甘油-3-磷酸胆碱组成的脂质膜的相互作用。为了在分子水平上确定两种药物的膜影响，应用了不同的实验（NMR、ESR、荧光）和理论（MD模拟）方法。数据显示，与伊马替尼相比，西替尼与膜的相互作用更有效，显著影响各种物理化学膜参数，如膜序和极性溶质的跨膜渗透。西替尼对膜的显著影响可以通过药物对POPC的强亲和力来解释，该亲和力通过减弱胆固醇的有序效应来与POPC-胆固醇的相互作用竞争。这些数据有助于理解这些药物的假定毒性和细胞毒性副作用，如触发细胞裂解或凋亡。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chemistry and Physics of Lipids 生物-生化与分子生物学

CiteScore

7.60

自引率

2.90%

发文量

审稿时长

40 days

期刊介绍： Chemistry and Physics of Lipids publishes research papers and review articles on chemical and physical aspects of lipids with primary emphasis on the relationship of these properties to biological functions and to biomedical applications. Accordingly, the journal covers: advances in synthetic and analytical lipid methodology; mass-spectrometry of lipids; chemical and physical characterisation of isolated structures; thermodynamics, phase behaviour, topology and dynamics of lipid assemblies; physicochemical studies into lipid-lipid and lipid-protein interactions in lipoproteins and in natural and model membranes; movement of lipids within, across and between membranes; intracellular lipid transfer; structure-function relationships and the nature of lipid-derived second messengers; chemical, physical and functional alterations of lipids induced by free radicals; enzymatic and non-enzymatic mechanisms of lipid peroxidation in cells, tissues, biofluids; oxidative lipidomics; and the role of lipids in the regulation of membrane-dependent biological processes.