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

  • Bioorg Med Chem. 2018 Feb 1;26(3):775-785. doi: 10.1016/j.bmc.2017.12.045.
Yosuke Ota  1 ,  Shin Miyamura  2 ,  Misaho Araki  2 ,  Yukihiro Itoh  1 ,  Shusuke Yasuda  1 ,  Mitsuharu Masuda  1 ,  Tomoyuki Taniguchi  1 ,  Yoshihiro Sowa  1 ,  Toshiyuki Sakai  3 ,  Kenichiro Itami  4 ,  Junichiro Yamaguchi  5 ,  Takayoshi Suzuki  6
Affiliations
  • 1. Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto 603-0823, Japan.
  • 2. Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan.
  • 3. Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto 603-0823, Japan; CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.
  • 4. Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan; JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan.
  • 5. Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan; Department of Applied Chemistry, Waseda University 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan. Electronic address: [email protected].
  • 6. Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto 603-0823, Japan; CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan. Electronic address: [email protected].
PMID: 29331452 DOI: 10.1016/j.bmc.2017.12.045
Abstract

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.

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