Isoindole-1,3-dione derivatives as RSK2 inhibitors: Synthesis, molecular docking simulation and SAR analysis

Article abstract of DOI:10.1039/c5md00469a

RSK2 (p90 ribosomal S6 kinase 2) is a serine/threonine kinase expressed in a variety of cancers. Molecular-targeted inhibition of RSK2 as a potential therapeutic strategy for human cancers has been documented. In this work, a series of isoindole-1,3-dione derivatives as novel RSK2 inhibitors were designed and synthesized from a hit discovered in our previous study. Some compounds were confirmed to be moderately potent RSK2 inhibitors with IC₅₀ values of about 0.5 μM. Structure-activity relationship analysis and binding mode studies by molecular docking were performed.

Full text of DOI:10.1039/c5md00469a

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Isoindole-1,3-dione Derivatives as RSK2 Inhibitors: Synthesis,
Molecular Docking Simulation and SAR Analysis
Received 00th January 20xx,
Accepted 00th January 20xx
Wei Zhoua, #, Shiliang Lia, #, Weiqiang Lua, #, Jun Yuana, Yufang Xua, Honglin Lia,*, Jin Huanga,*
Zhenjiang Zhaoa,*
,
DOI: 10.1039/x0xx00000x
RSK2 (p90 ribosomal S6 kinase 2) is a serine/threonine kinase expressed in a variety of cancers. Molecular-targeted
inhibition of RSK2 as a potential therapeutic strategy for human cancers has been documented. In this work, a series of
isoindole-1,3-dione derivatives as novel RSK2 inhibitors were designed and synthesized from a hit discovered in our
previously study. Some compounds were confirmed to be moderate potent RSK2 inhibitors with the IC50 values at about
0.5 μM range. The structure-activity relationship analysis and binding mode studies by molecular docking were performed.
www.rsc.org/
H
H
N
OH
O
O
N
O
O
Introduction
HO
O
O
RSK1~4 (p90 ribosomal S6 protein kinase) belong to a family of
4 serine/threonine kinases, in which RSK2 plays a crucial role in
the mitogen-activated protein kinase (MAPK) signaling
pathway.1, 2 It has been verified that the overexpression and
aberrant activation of RSK2 are related to many human
cancers and other diseases, such as breast cancer, prostate
cancer,3 myeloid leukemia,4 HIV infection5 and Coffin-Lowry
syndrome (CLS).6 Therefore, RSK2 is a promising anti-cancer
target and the discovery of potent inhibitors against RSK2 is of
great significance.
O
N
N
N
N
OH
OH
OAc
H
O
S
N
OAc
HN
NH2
Ro31-8220
SL0101
GF109203X
HO
O
N
N
F
N
HN
N
N
O
O
1 (Hit compound)
RSK2 has a unique structure that it possesses an N-
terminal kinase domain (NTKD) and a C-terminal kinase
domain (CTKD) connected by a linker region.7 Thus there are
two binding sites for ATP-competitive inhibitors in the NTKD
and the CTKD, respectively.8, 9 To date, some RSK2 inhibitors
with diverse scaffolds have been developed (Figure 1).10-12
SL0101 isolated from the tropical plant Forsteroniarefracta is
the first reported RSK2 specific inhibitor. SL0101 was reported
to interact with RSK2 at the NTKD ATP-binding pocket and
showed good inhibitory activity with an IC50 value of 89 nM.13,
Me
FMK
Fig. 1 Examples of reported RSK2 inhibitors and the hit
compound
1.
value of 15 nM.16 Most recently, Shafer et al. reported a series
of 2-Amino-7-substituted benzoxazole compounds as potent
and selective RSK2 inhibitors with nanomolar IC50 value.12
However, none of these RSK2 inhibitors have been used in the
clinical trials until now. Therefore, there is urgent need to
develop other scaffold RSK2 inhibitors as anticancer drugs.
We recently developed SHAFTS program, a hybrid 3D
similarity calculation method combining chemical feature
matching and molecular shape superposition.17 Several
inhibitors for the NTKD of RSK2 were identified successfully
using SHAFTS program in our previous study.18-21 Among them,
14
Several other RSK2 inhibitors were also found to potently
but nonselectively inhibit RSK2, such as PKC (protein kinase C)
inhibitors GF109203X (IC50 = 50 nM against RSK2) and Ro31-
8220 (IC50 = 3 nM against RSK2).15 In addition, FMK is a
selective and irreversible RSK2 CTKD inhibitor with an IC50
a hit compound 1 with isoindole-1,3-dione scaffold (one drug-
like chemical fragment22, 23) showed some RSK2 affinity with an
inhibitory ratio of 44% at 10 μM. In this study, the structural
optimization and synthesis from the hit compound
1 as novel
RSK2 inhibitors were carried out. Some compounds exhibited
much improved inhibitory activity against RSK2 compared with
the hit, the most active compound
7 inhibited RSK2 activity
with an IC50 value up to 0.47 μM (inhibitory ratio of 97% at 10
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μM). The structure-activity relationship (SAR) analyses and
molecular docking simulation explanations were also
performed for searching more potent RSK2 inhibitors.
Inhibition
IC50
R1
R2
R3
Results and discussion
Compd
(%)
(μM)
NDb
8.74
ND
Structural Optimization and SAR Interpretation
1
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
43.57
56.66
8.52
F
To improve the inhibitory potency of hit compound and
explore the structure-activity relationships, we designed a
series of isoindole-1,3-dione derivatives as novel RSK2
inhibitors. The enzyme inhibitory activities toward RSK2 of the
designed compounds were evaluated and the results were
summarized in Table 1.
3
Cl
4
Me
Et
54.00
62.99
46.54
97.19
28.05
4.3
5
4.31
ND
6
i-Pr
OMe
OCF3
OH
OEt
7
0.47
ND
We first investigated the effects of substituent R1 on
arylamine part. Replacing the R1 in hit compound
8
9
100.92 0.52
100.12 0.59
1
with
10
electron-withdrawing halogen atoms (2 and 3) did not induce
the improvement of inhibitory activities. Compounds
substituted with weak electron-donating alkyl moieties, such
11
81.04
0.86
as methyl (4), ethyl (5) and isopropyl (6), presented slightly
improved potency against RSK2. We were pleased to find that
the enzymatic inhibitory activities increased significantly while
12
13
14
15
16
17
18
19
20
21
22
23
morpholinyl
OMe
H
H
101.43 0.79
Me
Ac
H
H
86.99
17.17
35.69
86.96
95.64
3.50
ND
a strong electron-donating methoxyl group (
was introduced to the R1 position. Same results reappeared for
other typical electron-donating groups such as hydroxyl ( ),
7, IC50 = 0.47 μM)
OMe
H
Me
5-NO2
5-NO2
4-NH2
5-NH2
ND
9
OEt
H
2.83
3.53
ethoxyl (10), diethylamino (11) and morpholinyl (12), their
inhibitory activities against RSK2 IC50 values were 0.52 μM,
0.59 μM, 0.86 μM and 0.79 μM, respectively. This tendency
was tested by replacing the methoxyl group (7) with an
OMe
H
OMe
H
109.10 0.59
OMe
H
4-benzamido 99.51
5-benzamido 82.00
0.99
2.16
OMe
H
electron-withdrawing group trifluoromethoxy moiety (8), its
OEt
H
4-benzamido 105.41 1.34
5-benzamido 69.47 4.58
inhibitory potency against RSK2 nearly disappeared. The
results indicated that electron-donating substituents in the R1
position might be more favoured for improving the inhibitory
potency against RSK2.
OEt
H
morpholinyl
H
5-benzamido 102.51 1.01
5-phenyl-
24
OMe
H
34.79
ND
carbamido
Next, we examined the impact of different substituents R2
on the inhibitory against RSK2. When R2 was methyl (13), the
inhibitory activity lowered more than 7 times by comparing
Ro31
98.21
0.01
-8220
aInhibitory rate was measured at the concentration of 10 μM
inhibitor. IC50 value was measured if the inhibitory rate at 10
μM exceeded 50%. bND, Not determined.
with compound
7
. When R2 was acetyl group (14), the
inhibitory potency against RSK2 completely disappeared.
These results suggested that the volume of substituents at R2
might affect the spatial molecular structure. More probably,
the impact on hydrogen bond formation might be the key
factor by comparing hydrogen bond tendency N-H>N-CH3>N-
COCH3. The investigations indicated that R2=H was necessary
for keeping the inhibitory activity against RSK2.
of compounds 17 and 18 were better tolerated with IC50 values
against RSK2 of 3.53 μM and 0.59 μM, respectively. We
expected that introducing hydrophobic groups could enhance
the binding affinity by increasing the hydrophobic interactions,
but benzolation of the R3 amino groups (17 and 18) led to
Since compound
7 mainly stretches along the hinge
corresponding compounds 19-23
,
just brought similar
region of RSK2 NTKD (Figure 2A) and enough space of the
binding pocket remain to be explored, we then focused on the
substituents R3 at C4 position or C5 position of the isoindole-
1,3-dione scaffold. While introducing an electron-withdrawing
group nitro on the C5 position, the enzymatic inhibitory
activities of compounds 15 and 16 decreased obviously
inhibitory activities. The results suggested that electron-
withdrawing group such as nitro on C4 position or C5 position
of the isoindole-1,3-dione scaffold had negative effects on the
inhibitory activity, while electron-donating groups such as NH2,
or a big group benzamide were all tolerated, at least, no
obvious adverse effects appeared comparing with compound
compared with the corresponding compounds
4 and 10. In
7.
Furthermore, when introducing
a
longer group
contrast, amino substituents at the C4 position and C5 position
Table 1 In Vitro Enzymatic Inhibitory Activities of Isoindole-1,3-
dione Compounds against RSK2a
phenylcarbamido onto C5 position (24), its inhibitory activity
against RSK2 diminished completely, this illustrated that the
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9.36 kcal/mol and -9.21 kcal/mol respectively. Just like the
other RSK2 inhibitors we reported previously,18-21 both of the
compounds occupied the ATP binding site and generated a bi-
dentate hydrogen bond with Leu150 at the hinge region.
Specifically, one of the oxygen atom in isoindole-1,3-dione was
capable to be hydrogen bonded to backbone nitrogen atom of
Leu150, and the NR2 group in the linker of
hydrogen bond with the backbone carbonyl group of Leu150
spontaneously. If the NR2 group of
is substituted by other
7 could also form a
7
groups (R2=CH3 13 and R2=COCH3 14), the hydrogen bond with
backbone carbonyl group of Leu150 would be destroyed,
leading to a decreased inhibitory activity. In addition, the
oxygen atom in 4-benzamido moiety of 19 acted as a hydrogen
bond acceptor to the side chain hydroxyl group of Thr210 with
the hydrogen bond distance of 2.5Å, and the phenyl group in
the 4-benzamido moiety contacted the residues scattering
around with van der Waals interactions. However, compared
Fig.
2
The proposed binding modes for representative
(A), 19 (B). The X-ray crystal structure of RSK2
compounds
7
NTKD (PDB ID: 4NW6) is shown as light blue cartoon, and the
docked inhibitors are represented as cyan sticks. Key residues
(thin sticks) in the ATP binding site are colored in blue.
Hydrogen atoms are hidden for clarity. Potential
intermolecular hydrogen bonds are showed in orange dashed
lines.
with 7, those extra hydrogen bond and VDW contacts of 19 did
not contribute to the binding affinity for the compounds of this
series. Nevertheless, electron-donating groups at R1 plays an
important role for the improvement of inhibitory activity of
the isoindole-1,3-dione derivatives, which could make VDW
contacts with residues Leu74, Phe149 and Gly153, combines
with the connected benzene ring. Therefore, compared with
volume and spatial orientation of phenylcarbamido didn't fit to
the enzyme active pocket.
Binding Mode Analysis
To further study the action mechanism of these series of
derivatives, the predicted binding modes of compounds
7 and
19 are shown in Figure 2A and 2B with the docking energy of -
R2
O
O
Ac
O
R1
N
O
b
N
a
NH
N
N
8
(
)
O
O
O
14
: R1 = H, R2 = H
: R1 = Cl, R2 = H
: R1 = F, R2 = H
25
1
3
2
4
: R1 = Me, R2 = H
5: R1 = Et, R2 = H
6: R1 = i-Pr, R2 = H
7: R1 = OMe, R2 = H 8: R1 = OCF3, R2 = H
9: R1 = OH, R2 = H 10: R1 = OEt, R2 = H
12: R1 = morpholinyl, R2 = H
: R1 = OMe, R2 = Me
13
O
O
O
O
O
H2N
O2N
O2N
O2N
HN
R1
HN
O
OH
N
f
e
c
d
NH
N
N
NH
O
O
O
O
O
27
: 5-NO2, R1 = Me
: 5-NO2, R1 = OEt
17
: 4-NH2, R1 = OMe
: 5-NH2, R1 = OMe
15
16
26
25
: 5-NO2
18
28: 4-NO2, R1 = OMe
29: 5-NO2, R1 = OMe
O
O2N
O
H2N
g
f
d, e
O
O
NH
O
NH
NH
HN
R1
NH
O
N
NH
O
O
30
26
O
O
31
: 4-benzamido, R1 = OMe
: 5-benzamido, R1 = OMe
19
20
21: 4-benzamido, R1 = OEt
22: 5-benzamido, R1 = OEt
23: 5-benzamido, R1 = morpholinyl
O
O
NH2
H
H
NCO
H
H
N
N
N
N
HN
O
a
h
i
N
NH
O
O
29
O
O
32
33
34
24
Scheme 1 Reagents and conditions: (a) formaldehyde, arylamine, EtOH, H2O, reflux, 50-85%; (b) CH3COOCl, Et3N, CH2Cl2, rt, 69%;
(c) HNO3, H2SO4, 40 oC, 65%; (d) formaldehyde, 1,4-dioxane, H2O, reflux; (e) ArNH2, EtOH, 50 oC, 51-80%; (f) 10%Pd/C, H2, MeOH,
97-99%; (g) acyl chloride, 1-methyl-2-pyrrolidinone, CH3CN, 0 °C to rt, 90
PhMe, 110 oC, 48%.
−
93%; (h) triphosgene (BTC), PhMe, reflux; (i) DMF,
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The synthesis of the isoindole-1,3-dione derivatives used in
this study was shown in Scheme 1. Several final products were
prepared by coupling of the starting material phthalimide with
a variety of arylamines.24 Acetylation of compound
amide compound 14 as a white solid. The nitro compound 26
was prepared by nitration of phthalimide 25 25
Treating
7 produced
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compound 26 with aqueous formaldehyde obtained
hydroxymethyl intermediate 27 which was followed by
coupling with p-anisidine to yield compound 28. The nitro
group of 28 was reduced with Pd/C hydrogenation in methanol
to produce compound 17 and 18 in good yields. Nitro
compound 26 was reduced with Pd/C hydrogenation and
further acylated by benzoyl chloride to yield 30
. Final
compounds 19-23 were prepared from 30 by a method similar
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.
Conclusions
In summary, a series of isoindole-1,3-dione derivatives were
designed and synthesized as RSK2 inhibitors through structural
optimization of the hit compound 1. The SAR analyses and the
proposed binding modes were explored to further elucidate
the SAR. Electron-donating substituents for R1 were favorable
for inhibitory activity, and un-substituted R2 was beneficial to
increase affinity with RSK2 by forming H-bond. Compound
7
showed much improved inhibitory activity compared with the
initial hit, with an IC50 value of 0.47 μM. It is necessary to
further optimization of this scaffold to achieve more potent
RSK2 inhibitors.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (grants 21372078, 81222046 and
81230076) (Z.Z., H.L.), the Shanghai Committee of Science and
Technology (grant 14431902400) (H.L.), the National S&T
Major Project of China (Grant 2013ZX09507004) and the
Twelfth Five-Year National Science & Technology Support
Program (Grant 2012BAI29B06) (H.L.). Honglin Li is also
sponsored by the Innovation Program of Shanghai Municipal
Education Commission (grant 13SG32) and Fok Ying Tung
Education Foundation (141035).
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DOI: 10.1039/C5MD00469A
Isoindole-1,3-dione Derivatives as RSK2 Inhibitors:
Synthesis, Molecular Docking Simulation and SAR Analysis
Wei Zhoua, #, Shiliang Li a, #, Weiqiang Lu a, #, Jun Yuana, Yufang Xua, Honglin Lia,*, Jin Huanga,*,
Zhenjiang Zhaoa,*
a State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design,
School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
* To whom correspondence should be addressed. Tel: +86-21-64250213; Fax: +86-21-64250213;
Email: huangjin@ecust.edu.cn, zhjzhao@ecust.edu.cn, hlli@ecust.edu.cn
# Authors contributed equally to this work.
The present study reports a series of novel potent RSK2 inhibitors from structure
modifications of the virtual screening hit.