2. Academic Validation
  3. Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors

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

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.

Figures
Products