Nicotinamide Phosphoribosyltransferase (NAMPT) Is a New Target of Antitumor Agent Chidamide

Article abstract of DOI:10.1021/acsmedchemlett.9b00407

Chidamide is a histone deacetylase (HDAC) inhibitor that is currently used to treat cutaneous T-cell lymphoma in clinic. Herein nicotinamide phosphoribosyltransferase (NAMPT) was identified to be a new target of chidamide on the basis of the pharmacophore analysis, molecular docking, biological assays, inhibitor design, and structure-activity relationship study. The polypharmacology of chidamide will provide important information for better understanding its antitumor mechanism. Also, design of dual NAMPT/HDAC inhibitors may serve as an effective strategy to develop novel antitumor agents.

Full text of DOI:10.1021/acsmedchemlett.9b00407

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Letter
Nicotinamide Phosphoribosyltransferase (NAMPT)
is a New Target of Antitumor Agent Chidamide
Ying Wu, Lei Wang, Yahui Huang, Shuqiang Chen, Shanchao Wu, Guoqiang Dong, and Chunquan Sheng
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00407 • Publication Date (Web): 13 Dec 2019
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Nicotinamide Phosphoribosyltransferase (NAMPT) is a New Target
of Antitumor Agent Chidamide
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†
†
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†
,†
Ying Wu , Lei Wang , Yahui Huang , Shuqiang Chen , Shanchao Wu , Guoqiang Dong * , Chunquan
Sheng*
,
†,‡
†Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, shanghai 200433, China
‡ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
KEYWORDS: Chidamide, histone deacetylase, nicotinamide phosphoribosyltransferase, dual inhibitors
ABSTRACT: Chidamide is a histone deacetylase (HDAC) inhibitor, which is currently used to treat cutaneous T-cell lymphoma in
clinic. Herein nicotinamide phosphoribosyltransferase (NAMPT) was identified to be a new target of chidamide on the basis of the
pharmacophore analysis, molecular docking, biological assays, inhibitor design and structure-activity relationship study. The
polypharmacology of chidamide will provide important information for better understanding its antitumor mechanism. Also, design
of dual NAMPT/HDAC inhibitors may serve as an effective strategy to develop novel antitumor agents.
The balance between acetylation and deacetylation of
histone plays an essential role in maintaining cell
homeostasis.1 These two processes are regulated by
histone acetyltransferase (HAT) and histone deacetylase
(HDAC) which increases and decreases gene
transcription, respectively.2 It has been reported that
salvage pathway using NAM as the precursor, in which
nicotinamide phosphoribosyltransferase (NAMPT) is the
rate-limiting enzyme16 (Figure 1A). Recently, NAMPT
is recognized as a promising target for the development
of novel antitumor agents. Although two NAMPT
inhibitors (FK866 and CHS828) have been progressed
into clinical trials for treatment of cutaneous T-cell
lymphoma and metastatic melanoma.17 However, further
drug development was hampered due to significant side
effects, which inspired the discovery of novel NAMPT
inhibitors. Previously, we identified a series of new
HDAC is overexpressed in various tumor cells.3,
4
HDAC inhibitors (Figure 1) can decrease the
acetylation level to modify the gene expression and
induce death of cancer cells.5 HDAC inhibitors (e.g.
vorinostat, romidepsin, belinostat, and panobinostat)
have been widely used in clinic for the treatment of
cutaneous T-cell lymphoma and multiple myeloma.6-8
Chidamide (1) is a benzamide HDAC inhibitor, which
was marketed in China for the treatment of cutaneous T-
cell lymphoma in 2015.9 Chidamide showed good
inhibitory activity against class I (HDAC1-3) and class
IIb HDACs (HDAC10), whereas it was poorly effective
towards other class I, IIa, and IV HDAC isoforms.10
Although its antitumor potency and antitumor
mechanism has been widely investigated,11-14 the
research for target profiling of chidamide is still rare,
which limits deeper understanding its antitumor
mechanism.
NAMPT
inhibitors
through
high-throughput
screening.18-20 Moreover, novel NAMPT/HDAC dual
inhibitors were rationally designed on the basis of the
synergistic effects between NAMPT and HDAC, which
showed excellent in vitro and in vivo antitumor efficacy
toward human colon cancer cell HCT116.21 Herein
NAMPT was proven to be a new target of chidamide by
pharmacophore analysis, molecular docking, inhibitor
design and biological assays, which provided new
insights for the antitumor mechanism of chidamide and
important information for new antitumor drug
development.
The pharmacophore of HDAC inhibitors consists of
Nicotinamide adenine dinucleotide (NAD+) plays
an essential role in cellular physiological processes.15
There are four synthetic routes of NAD+, including the
de novo pathway synthesized from tryptophan (Trp), the
alternative salvage pathway synthesized from nicotinic
acid (NA) or nicotinamide ribose (NR) and the primary
salvage pathway synthesized from nicotinamide (NAM).
In mammalian cells, NAD+ relies on the primary
three parts (Figure 1B): cap, linker and zinc binding
region
(ZBG,
hydroxamic
acid
or
o-
phenylenediamine)22. Similar to HDAC inhibitors, the
pharmacophore of NAMPT inhibitors also includes cap,
linker and hydrophobic tails (Figure 1C). For
chidamide, its (E)-3-(pyridin-3-yl)acrylamide ZBG
could be regarded as a bioisostere of the hydrophobic
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tail in NAMPT inhibitors. Thus, we envisioned that
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chidamide might be a NAMPT inhibitor.
(A)
NAD salvage pathway
De Novo Pathway
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8
NAM
NAM
NR
NA
Trp
extracellular
intracellular
NAPRT
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NA
NR
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NAMPT
NAD+ Synthatase
NRK
NAD+
NMN
(B)
(C)
Cap
Linker Zinc binding group
Cap
Linker
Tail
O
N
H2N
F
N
O
HN
O
H
N
N
H
Figure 2. Predicted binding mode of chidamide in the active site
of NAMPT (PDB: 2GVJ). (A) Predicted binding pose of
chidamide in the active region of NAMPT. Hydrogen bonds
(yellow) are represented with dash lines. The figure was generated
using PyMol (http://www. Pymol.org/). (B) Superimposition of
FK866 (green) and chidamide (purple) in the active region of
NAMPT. The figure was generated using PyMol (http://www.
N
O
FK866 (2)
Chidamide (1)
Figure 1. (A) Pathway of NAD+ biosynthesis; (B)
Pharmacophore of HDAC inhibitors; (C) Pharmacophore of
NAMPT inhibitors.
Pymol.org/).
To validate the hypothesis, molecular docking was
initially carried out to investigate whether chidamide
shares a similar binding mode to NAMPT inhibitors.
Chidamide was docked into the active site of NAMPT
(PDB code: 2GVJ)23 using docking software Gold24.
The results showed that chidamide bound to the same
pocket of FK866 in the active site of NAMPT (Figure
2). As shown in Figure 2A, the pyridyl group of
chidamide formed face to face π-π interactions with
TYR18, PHE193 and ARG311, respectively, which
were similar to that of FK866. The carbonyl oxygen and
nitrogen atom of the pyridyl amide group formed two
hydrogen bonds with SER275 and ASP219,
respectively, while FK866 only formed a hydrogen bond
with SER275. The results suggested that chidamide
could bind to the active site of NAMPT. Thus, the
inhibitory activity of chidamide against human
recombinant NAMPT was tested using the fluorometric
assay described in our previous studies.19 As shown in
Table 1, chidamide was proven to be a NAMPT
inhibitor with an IC50 value of 2.1 M.
Figure 3. Binding of chidamide with NAMPT using CETSA. (A)
Western blot of CETSA for NAMPT with FK866 (10 M) and
chidamide (10 M) in HCT116 cells after the treatment for 2 h.
(B) CESTA melt curves in HCT116 cells for NAMPT with
FK866 and chidamide (at 10 μM).
Cellular thermal shift assay (CETSA)21 was further
performed to investigate whether NAMPT is the direct
binding target of chidamide in HCT116 cells using
FK866 as the positive control. The results indicated that
the NAMPT expression level of cells treated with
chidamide was more stable compared with the control,
The decrease in NAD+ level is a classic feature
after inhibition of NAMPT activity.21 Therefore, we
measured the NAD+ variation qualitatively compared
with the control group. As shown in Figure 4A,
chidamide effectively decreased the cellular NAD+ level
after incubation with human HCT116 cells for 24 h.
indicating
a good binding affinity between the
chidamide and NAMPT protein (Figure 3).
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compounds 7a and 7b without the pharmacophore of
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8
NAMPT inhibitors lost NAMPT inhibitory activity.
Interestingly, their HDAC1 inhibitory activities were
improved, while HDAC2 and HDAC3 inhibitory
activities were comparable to chidamide (Table 1). For
the antitumor activity, they retained good potency
against K562 cell line, whereas the growth inhibitory
activity against HCT116, HL60 and HEL cell lines were
decreased.
Similarly,
after
the
removal
of
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pharmacophore of HDAC inhibitors, compounds 7c and
7d lost HDAC inhibitory activity but retained the
NAMPT inhibitory activity. However, their antitumor
activities were significantly decreased. Compounds 7a-
7d and chidamide were also assayed cytotoxicity against
cancer cells deficient in NAMPT using siRNA26. The
results indicated that NAMPT inhibitors chidamide, 7a
and 7b showed decreased inhibitory activity in NAMPT-
deficient cells, further confirming that NAMPT is a
target of chidamide. The detailed contribution of
HDAC1-3 and NAMPT to the antitumor activity of
chidamide still remains to be further explored.
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Figure 4. (A) Relative NAD+ level in HCT116 cells treated with
chidamide at different concentrations for 24 h. Rescue studies
with the addition of NA (4 M) or NMN (10 M) in HCT116
cells (B), K562 cells (C), HL60 cells (D) and HEL cells (E).
Scheme1 Chemical synthesis of target compoundsa
The addition of NA could activate the alternative
rescue pathway to synthesize NAD+. Furthermore, the
addition of the downstream product NMN could skip the
exertion of activity of NAMPT to obtain NAD+. Herein,
rescue studies25 showed that addition of NA (4 M) or
NMN (10 M) could significantly rescue cells from
treatment with chidamide in HCT116 cells and human
leukemia cells including K562, HL60 and HEL (Figure
4B-4E), further confirming that NAMPT is a target of
chidamide.
O
O
O
OH
a
O
b
N
H
H2N
H2N
Y
O
X
3
4
5a-c
O
5a
, X = H, Y = H
, X = H, Y = N
, X = N, Y = H
5b
5c
O
O
c
d
N
N
H
R1
H
N
H
Y
OH
Y
X
X
O
O
6a-c
7a-d
R2
7a
, X = H, Y = H, R1 = NH2, R2 = F
, X = H, Y = N, R1 = NH2, R2= F
, X = N, Y = H, R1 = H, R2 = F
6a
6b
6c
, X = H, Y = H
, X = H, Y = N
, X = N, Y = H
7b
7c
7d
, X = N, Y = H, R1 = H, R2 = H
To investigate the role of NAMPT in exerting the
antitumor activity of chidamide, four chidamide analogs
7a-d (Scheme 1) were designed as the control molecules
by removing the pharmacophores of HDAC (o-
phenylenediamine) or NAMPT ((E)-3-(pyridin-3-
yl)acrylamide) inhibitors. Enzyme inhibition and in vitro
antitumor activity assay (Table 1) showed that
a Reagents and conditions: (a) CH3OH, H2SO4, reflux, 6 h, yield
92%; (b) (E)-3-(pyridin-4-yl)acrylic acid or (E)-3-(pyridin-3-
yl)acrylic acid or cinnamic acid, HATU, DIPEA, DMF, rt, 2 h,
yield 85%-93%; (c) LiOH, THF/MeOH/H2O, rt, 4 h, yield 80%-
92%; (d) different substituted anilines, HATU, DIPEA, DMF, rt,
2 h, yield 76%-88%.
Table 1. Enzyme inhibition and in vitro antitumor activity of target compounds (IC50, M)
Compounds
NAMPT
HDAC1
HDAC2
HDAC3
HCT116
K562
chidamide
2.1  
7a
7b
7c
7d
>100
>100
2.5  0.20
>100
3.9  1.1
>100
0.13  0.0020
0.026  0.004 0.033  0.0070
0.11  0.0004 0.14 0.0016 0.15  0.0015
>100
>100
>20
>100
>100
>20
0.33  0.028
0.34  0.064
0.36 0.018
2.6  0.45
0.38  0.17
1.5  0.56
1.5  0.55
0.32  0.0064
2.4  0.87
0.32  0.063
0.14  0.08
0.37  0.042
1.2  0.52
0.70  0.16 4.1  1.2
11  1.2 8.4  2.0
5.0  0.67 4.7  0.65
HL60
0.0022  0.0010
HEL
0.013  0.0071
> 20
HCT116-siRNA
K562-siRNA
HL60-siRNA
HEL-siRNA
> 20
> 20
> 20
> 20
> 20
> 20
> 20
> 20
9.7  1.9
0.40  0.12
0.89  0.080
2.3  0.090
6.1  0.31
0.27  0.06
0.48  0.03
1.4  0.21
2.4  0.26
3.2  0.40
1.8  0.23
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NRK: nicotinamide ribose kinase; NAPRT, nicotinic acid
In summary, NAMPT was identified to be a new
target of chidamide on the basis of the similarity of
pharmacophore between HDAC and NAMPT inhibitors.
Chidamide had low micromolar inhibitory activity
towards NAMPT and significantly decreased cellular
NAD+ level, which shares a similar binding mode to
NAMPT inhibitor FK866. The results are helpful for
better understanding of antitumor mechanism of
chidamide. The modification of chidamide by removal
of HDAC pharmacophore and NAMPT pharmacophore
significantly decreased its antitumor activity, indicating
that dual inhibition of HDAC and NAMPT might lead to
improved antitumor activity. In our previous studies, the
balanced inhibitory activity against both targets was
found to be important for the anti-tumor activity.21
Considering the synergistic effects of HDAC and
NAMPT, HDAC/NAMPT dual inhibitors might be a
promising strategy for the development of novel
antitumor agents.
phosphoribosyltransferase; Trp: tryptophan; NAM, nicotinamide;
NMN, nicotinamide mononucleotide; ZBG, zinc-binding group;
CETSA, cellular thermal shift assay; NA, nicotinic acid.
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ABBREVIATIONS
NAMPT, nicotinamide phosphoribosyltransferase; HDAC,
histone deacetylase; NAD+, nicotinamide adenine dinucleotide;
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