Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Molecules. 2020 Mar 4;25(5):1149. doi: 10.3390/molecules25051149.
Tyrosine kinase inhibitors revolutionized cancer therapy but still evoke strong adverse effects that can dramatically reduce patients' quality of life. One possibility to enhance drug safety is the exploitation of prodrug strategies to selectively activate a drug inside the tumor tissue. In this study, we designed a prodrug strategy for the approved c-MET, ALK, and ROS1 tyrosine kinase inhibitor crizotinib. Therefore, a boronic-acid trigger moiety was attached to the 2-aminopyridine group of crizotinib, which is a crucial position for target kinase binding. The influence of the modifications on the c-MET- and ALK-binding ability was investigated by docking studies, and the strongly reduced interactions could be confirmed by cell-free kinase inhibition assay. Furthermore, the newly synthesized compounds were tested for their activation behavior with HO and their stability in cell culture medium and serum. Finally, the biological activity of the prodrugs was investigated in three cancer cell lines and revealed a good correlation between activity and intrinsic HO levels of the cells for prodrug . Furthermore, the activity of this prodrug was distinctly reduced in a non-malignant, c-MET expressing human lung fibroblast (HLF) cell line.
酪氨酸激酶抑制剂彻底改变了癌症治疗方法，但仍会引起强烈的不良反应，从而大大降低患者的生活质量。提高药物安全性的一种可能性是利用前药策略在肿瘤组织内选择性激活药物。在这项研究中，我们设计了一种针对已批准的 c-MET、ALK 和 ROS1 酪氨酸激酶抑制剂克唑替尼的前药策略。因此，在克唑替尼的 2-氨基吡啶基团上连接了硼酸触发部分，这是靶激酶结合的关键位置。通过对接研究研究了修饰对 c-MET 和 ALK 结合能力的影响，并通过无细胞激酶抑制测定证实了相互作用的强烈降低。此外，还测试了新合成的化合物与 HO 的激活行为及其在细胞培养液和血清中的稳定性。最后，在三种癌细胞系中研究了前药的生物学活性，并发现前药的活性与细胞内固有 HO 水平之间存在良好的相关性。此外，这种前药在非恶性、表达 c-MET 的人肺成纤维细胞（HLF）系中的活性明显降低。
