靶向癌症的 PCPA-药物偶联物： LSD1 抑制触发 4-羟基他莫昔芬的释放。
Targeting Cancer with PCPA-Drug Conjugates: LSD1 Inhibition-Triggered Release of 4-Hydroxytamoxifen.
机构信息
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
出版信息
Angew Chem Int Ed Engl. 2016 Dec 23;55(52):16115-16118. doi: 10.1002/anie.201608711. Epub 2016 Nov 24.
Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer-targeting methods. Herein, we focused on lysine-specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans-2-phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA-drug conjugate (PDC) prototypes, we designed PCPA-tamoxifen conjugates 1 a and 1 b, which released 4-hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells.
用小分子前药靶向癌症应该有助于克服与传统癌症靶向方法相关的问题。在这里，我们专注于赖氨酸特异性去甲基酶 1（LSD1），以触发在 LSD1 高度表达的癌细胞中抗癌药物的控制释放。LSD1 抑制剂反式-2-苯基环丙胺（PCPA）的缀合物被用作新型前药，通过 LSD1 抑制来选择性地释放抗癌药物。作为 PCPA-药物缀合物（PDC）的原型，我们设计了 PCPA-他莫昔芬缀合物 1a 和 1b，它们在 LSD1 存在下在体外释放 4-羟基他莫昔芬。此外，1a 和 1b 通过同时抑制 LSD1 和雌激素受体来抑制乳腺癌细胞的生长，而对正常细胞没有细胞毒性。这些结果表明 PDC 提供了一种有用的前药方法，可能有助于在癌细胞中选择性释放药物。
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