title: Targeting Cancer with PCPA-Drug Conjugates: LSD1 Inhibition-Triggered Release of 4-Hydroxytamoxifen.
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.
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ota
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Kaise
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
authors.forename: Kiminori
authors.initials: K
authors.lastname: Ohta
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Endo
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Masuda
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sowa
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.|CREST Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D065546:Drug Liberation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004847:Epithelial Cells; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D014191:Tranylcypromine; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: drug design; epigenetics; prodrugs; small molecules; targeted cancer therapy