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

Article abstract of DOI:10.1016/j.bmc.2017.12.045

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.

Full text of DOI:10.1016/j.bmc.2017.12.045

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Accepted Manuscript
Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibi-
tors
Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda,
Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai,
Kenichiro Itami, Junichiro Yamaguchi, Takayoshi Suzuki
PII:
S0968-0896(17)32293-9
https://doi.org/10.1016/j.bmc.2017.12.045
BMC 14150
DOI:
Reference:
Bioorganic & Medicinal Chemistry
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Revised Date:
Accepted Date:
24 November 2017
25 December 2017
28 December 2017
Please cite this article as: Ota, Y., Miyamura, S., Araki, M., Itoh, Y., Yasuda, S., Masuda, M., Taniguchi, T., Sowa,
Y., Sakai, T., Itami, K., Yamaguchi, J., Suzuki, T., Design, synthesis and evaluation of γ-turn mimetics as LSD1-
selective inhibitors, Bioorganic & Medicinal Chemistry (2017), doi: https://doi.org/10.1016/j.bmc.2017.12.045
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Design, synthesis and evaluation of γ-turn
mimetics as LSD1-selective inhibitors
Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki
Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Kenichiro Itami, Junichiro Yamaguchi, and Takayoshi Suzuki

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Bioorganic & Medicinal Chemistry
journal homepage: www.els evier.com
Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors
Yosuke Otaa, Shin Miyamurab, Misaho Arakib, Yukihiro Itoha, Shusuke Yasudaa, Mitsuharu Masudaa,
Tomoyuki Taniguchia, Yoshihiro Sowaa, Toshiyuki Sakaia, c, Kenichiro Itamib,d, Junichiro Yamaguchib,e,∗
and Takayoshi Suzukia,c,∗
,
a Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto, 603-0823, Japan
b Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya, 464-8602, Japan
c CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
d JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan
e Department of Applied Chemistry, Waseda University 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
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.
Received in revised form
Accepted
Available online
Keywords:
Lysine-specific demethylase 1 (LSD1)
Inhibitor
γ-turn mimetics
Fukuyama amine synthesis
Structure-activity relationship (SAR) study
2009 Elsevier Ltd. All rights reserved
.
———
∗ Corresponding author. Tel.: +81-3-5286-3225; e-mail: junyamaguchi@waseda.jp (J.Y.)
∗ Corresponding author. Tel.: +81-75-703-4937; fax: +81-75-703-4937; e-mail: suzukit@koto.kpu-m.ac.jp (T. Suzuki)

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1. Introduction
to their low cell membrane permeability.18 Therefore, we also
developed small-molecule-based LSD1 inhibitors consisting of a
PCPA moiety and a lysine moiety, such as NCD18 and NCD38,
as novel LSD1-selective inhibitors (Figure 1B).18 In particular,
NCD38 was found to have unique anticancer activities in both in
cellulo and in vivo studies.24,25 Recently, we performed a
structure–activity relationship study of NCD38 analogs in which
Lysine-specific demethylase
1
(LSD1) catalyzes the
demethylation at position 4 of the monomethyl/dimethyl lysine
residue on histone H3 (H3K4me1/2) by flavin adenine
dinucleotide (FAD)-dependent amine oxidation.1 LSD1 binds to
nuclear proteins (e.g., histone deacetylases,2 histone
methyltransferases,3 and nuclear receptors4) via CoREST as the
corepressor to epigenetically regulate the expression of genes
associated with tumorigenesis,5 globin synthesis,6 neuron
development,7 and so on. Thus, LSD1 is an attractive molecular
target for the therapy of cancer, globin disorders, and
neurodegenerative disorders. A number of LSD1 inhibitors have
been reported so far8–10 and they are categorized into two types
(i.e., irreversible and reversible inhibitors). Most of the
previously reported LSD1 inhibitors are irreversible ones that
react with FAD in the active site of LSD1.8–10 A representative
example of irreversible LSD1 inhibitors is trans-2-
phenylcyclopropylamine (PCPA),11 which is a non-selective
LSD1 inhibitor that also inhibits strongly other FAD-dependent
oxidases, such as monoamine oxidases (MAOs). Currently,
PCPA analogs, such as ORY-100112 and GSK2879552,13 are
being evaluated in clinical trials for the treatment of acute
myeloid leukemia and small lung cancer.
In 2007, Cole, Yu, and co-workers reported the co-crystal
structure of LSD1 with a suicide substrate consisting of N-
methylpropargylamine and histone H3 peptide; the substrate
forms a γ-turn structure in the active pocket of LSD1,14 in which
two individual amides form a hydrogen bond, as shown in
Figure 1A.15 It suggested that the γ-turn structure is important for
the substrate binding to the active pocket of LSD1.
Scheme 1. Synthesis of γ-turn units 2.
the PCPA moiety of NCD38 was replaced with various trans-2-
arylcyclopropylamines (ACPAs) to improve the LSD1 inhibitory
activity and anticancer activity of NCD38 (Figure 1B).26 Herein
we report the design, synthesis, and evaluation of γ-turn mimetics
1 of NCD18, NCD38, and their ACPA derivatives, with an eye to
further improving LSD1 inhibitory activity and anticancer
activity.
We previously reported irreversible LSD1-selective inhibitors,
including peptide- or small-molecule-based PCPA analogs.16–23
We were able to identify histone H3 peptide based LSD1
inhibitors that bear a PCPA moiety at position 4 of the lysine
residue on histone H3 peptides, which potently and selectively
inhibit LSD1 activity.18 These previous studies also suggested the
importance of the γ-turn structure for potent LSD1 inhibition.
2. Results and discussion
2.1. Design of γ-turn mimetics
Although H3 peptides bearing PCPA exhibit potent and
selective LSD1 inhibitory activities, they were not cell-active due