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.
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 -