Synthesis, Characterization and in vitro Studies of a Cathepsin B-Cleavable Prodrug of the VEGFR Inhibitor Sunitinib
Synthesis, Characterization and in vitro Studies of a Cathepsin B-Cleavable Prodrug of the VEGFR Inhibitor Sunitinib
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DOI：
10.1002/cbdv.201800520
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发表时间：
2019-01-01
影响因子：
2.9
通讯作者：
Keppler, Bernhard K.
中科院分区：
文献类型：
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作者：
Karnthaler-Benbakka, Claudia;Koblmueller, Bettina;Keppler, Bernhard K.
几十年来，由于其克服与化疗相关的常见问题的潜力，前药概念在癌症研究中引起了相当大的兴趣。然而，对于小分子酪氨酸激酶抑制剂，这也会导致严重的副作用，几乎没有任何策略，以产生前药的治疗改善迄今已被报道。在这里，我们提出的合成和生物学研究的组织蛋白酶B-切割前体药物的VEGFR抑制剂舒尼替尼。细胞活力测定和蛋白质印迹分析显示，与非组织蛋白酶B可裂解的参比化合物相比，前药在高度表达组织蛋白酶B的细胞系Caki-1和RU-MH中显示出与原始药物舒尼替尼相当的活性。此外，组织蛋白酶B裂解测定证实了前药的所需酶促活化。总之，所获得的数据表明，组织蛋白酶B可裂解的前药的概念可以转移到靶向治疗剂的类别，从而允许开发用于治疗癌症的优化的酪氨酸激酶抑制剂。
Since several decades, the prodrug concept has raised considerable interest in cancer research due to its potential to overcome common problems associated with chemotherapy. However, for small-molecule tyrosine kinase inhibitors, which also cause severe side effects, hardly any strategies to generate prodrugs for therapeutic improvement have been reported so far. Here, we present the synthesis and biological investigation of a cathepsin B-cleavable prodrug of the VEGFR inhibitor sunitinib. Cell viability assays and Western blot analyses revealed, that, in contrast to the non-cathepsin B-cleavable reference compound, the prodrug shows activity comparable to the original drug sunitinib in the highly cathepsin B-expressing cell lines Caki-1 and RU-MH. Moreover, a cathepsin B cleavage assay confirmed the desired enzymatic activation of the prodrug. Together, the obtained data show that the concept of cathepsin B-cleavable prodrugs can be transferred to the class of targeted therapeutics, allowing the development of optimized tyrosine kinase inhibitors for the treatment of cancer.