Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors

Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Kenichiro Itami, Junichiro Yamaguchi, Takayoshi Suzuki

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    7 Citations (Scopus)


    Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.

    Original languageEnglish
    Pages (from-to)775-785
    Number of pages11
    JournalBioorganic and Medicinal Chemistry
    Issue number3
    Publication statusPublished - 2018 Feb 1



    • Fukuyama amine synthesis
    • Inhibitor
    • Lysine-specific demethylase 1 (LSD1)
    • Structure-activity relationship (SAR) study
    • γ-Turn mimetics

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine
    • Molecular Biology
    • Pharmaceutical Science
    • Drug Discovery
    • Clinical Biochemistry
    • Organic Chemistry

    Cite this

    Ota, Y., Miyamura, S., Araki, M., Itoh, Y., Yasuda, S., Masuda, M., Taniguchi, T., Sowa, Y., Sakai, T., Itami, K., Yamaguchi, J., & Suzuki, T. (2018). Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors. Bioorganic and Medicinal Chemistry, 26(3), 775-785.