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

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.

• Authors: Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Kenichiro Itami, Junichiro Yamaguchi, Takayoshi Suzuki
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 26 Issue 3 Pg. 775-785 (02 01 2018) ISSN: 1464-3391 [Electronic] England
• PMID: 29331452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyclopropanes
• Enzyme Inhibitors
• cyclopropylamine
• Histone Demethylases
• Monoamine Oxidase
• KDM1A protein, human

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Catalytic Domain
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclopropanes (chemical synthesis, chemistry, pharmacology)
• Drug Design
• Enzyme Assays
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Histone Demethylases (antagonists & inhibitors, metabolism)
• Humans
• Monoamine Oxidase (chemistry, metabolism)