Targeting Cancer with PCPA‐Drug Conjugates: LSD1 Inhibition‐Triggered Release of 4‐Hydroxytamoxifen |
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| Authors: | Yosuke Ota Dr. Yukihiro Itoh Asako Kaise Dr. Kiminori Ohta Prof. Yasuyuki Endo Dr. Mitsuharu Masuda Dr. Yoshihiro Sowa Prof. Toshiyuki Sakai Prof. Takayoshi Suzuki |
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| Affiliation: | 1. Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Sakyo-Ku, Kyoto, Japan;2. Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Aoba-ku, Sendai, Japan;3. CREST Japan Science and Technology Agency (JST), Saitama, Japan |
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| Abstract: | 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. |
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| Keywords: | drug design epigenetics prodrugs small molecules targeted cancer therapy |
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