TY - JOUR
T1 - Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors
AU - Ota, Yosuke
AU - Miyamura, Shin
AU - Araki, Misaho
AU - Itoh, Yukihiro
AU - Yasuda, Shusuke
AU - Masuda, Mitsuharu
AU - Taniguchi, Tomoyuki
AU - Sowa, Yoshihiro
AU - Sakai, Toshiyuki
AU - Itami, Kenichiro
AU - Yamaguchi, Junichiro
AU - Suzuki, Takayoshi
N1 - Funding Information:
We thank Mie Morita for technical support. This work was supported by KAKENHI ( 16H01140 and 16H04148 to J.Y.) from MEXT , the Project for Cancer Research and Therapeutic Evolution (T. Suzuki) and the JST CREST program ( JPMJCR14L2 to T. Suzuki). ITbM is supported by the World Premier International Research Center (WPI) Initiative, Japan.
Funding Information:
We thank Mie Morita for technical support. This work was supported by KAKENHI (16H01140 and 16H04148 to J.Y.) from MEXT, the Project for Cancer Research and Therapeutic Evolution (T. Suzuki) and the JST CREST program (JPMJCR14L2 to T. Suzuki). ITbM is supported by the World Premier International Research Center (WPI) Initiative, Japan.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
KW - Fukuyama amine synthesis
KW - Inhibitor
KW - Lysine-specific demethylase 1 (LSD1)
KW - Structure-activity relationship (SAR) study
KW - γ-Turn mimetics
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U2 - 10.1016/j.bmc.2017.12.045
DO - 10.1016/j.bmc.2017.12.045
M3 - Article
C2 - 29331452
AN - SCOPUS:85040233617
VL - 26
SP - 775
EP - 785
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 3
ER -