Cancer-cell-selective targeting by arylcyclopropylamine-vorinostat conjugates
Cancer-cell-selective targeting by arylcyclopropylamine-vorinostat conjugates
复制标题
芳基环丙胺-伏立诺他偶联物选择性靶向癌细胞
DOI：
10.1021/acsmedchemlett.2c00126
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发表时间：
2022
影响因子：
4.2
通讯作者：
Suzuki T
中科院分区：
文献类型：
--
作者：
Ota Y;Itoh Y;Kurohara T;Singh R;Elboray EE;Hu C;Zamani F;Mukherjee A;Takada Y;Yamashita Y;Morita M;Horinaka M;Sowa Y;Masuda M;Sakai T;Suzuki T
通过小分子的抗癌药物递送提供了许多优于常规大分子药物递送系统的优点。我们先前开发了苯基环丙胺（PCPA）-药物缀合物（PDC）作为小分子药物递送载体，用于靶向赖氨酸特异性脱甲基酶1（LSD 1）过表达的癌症。在这项研究中，我们将这种PDC策略应用于HDAC抑制性抗癌剂伏立诺他。在三种合成的PCPA或芳基环丙胺（ACPA）-伏立诺他缀合物1、9和32中，具有4-氧苄基接头的缀合物32在缓冲溶液中显示出足够的稳定性、有效的LSD 1抑制、有效的LSD 1依赖性伏立诺他释放以及对表达LSD 1的人乳腺癌和小细胞肺癌细胞系的有效和选择性抗增殖活性。这些结果表明缀合物在癌细胞中选择性地释放伏立诺他。类似的策略可能适用于其他抗癌药物。
Anticancer drug delivery by small molecules offers a number of advantages over conventional macromolecular drug delivery systems. We previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) as small-molecule-based drug delivery vehicles for targeting lysine-specific demethylase 1 (LSD1)-overexpressing cancers. In this study, we applied this PDC strategy to the HDAC-inhibitory anticancer agent vorinostat. Among three synthesized PCPA or arylcyclopropylamine (ACPA)-vorinostat conjugates1,9, and32, conjugate32with a 4-oxybenzyl linker showed sufficient stability in buffer solutions, potent LSD1 inhibition, efficient LSD1-dependent vorinostat release, and potent and selective antiproliferative activity toward LSD1-expressing human breast cancer and small-cell lung cancer cell lines. These results indicate that the conjugate selectively releases vorinostat in cancer cells. A similar strategy may be applicable to other anticancer drugs.