A Triazolotriazine-Based Dual GSK-3β/CK-1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition

Article abstract of DOI:10.1002/cmdc.201800778

Glycogen synthase kinase 3β (GSK-3β) and casein kinase 1δ (CK-1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking-based design. Compound 12, 3-(7-amino-5-(cyclohexylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, showed combined inhibitory activity against GSK-3β and CK-1δ [IC₅₀(GSK-3β)=0.17 μm; IC₅₀(CK-1δ)=0.68 μm]. In particular, classical ATP competition was observed against CK-1δ, and a co-crystal of compound 12 inside GSK-3β confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK-3β. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK-3β/CK-1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.

Full text of DOI:10.1002/cmdc.201800778

Accepted Article
Title: A Triazolotriazine-based Dual GSK-3β/CK-1δ Ligand as a
Potential Neuroprotective Agent Presenting Two Different
Mechanisms of Enzymatic Inhibition
Authors: Sara Redenti, Irene Marcovih, Teresa De Vita, Conception
Perez, Rita De Zorzi, Nicola Demitri, Daniel I. Perez, Giovanni
Bottegoni, Paola Bisignano, Maicol Bissaro, Stefano Moro,
Ana Martinez, Paola Storici, Giampiero Spalluto, Andrea
Cavalli, and Stephanie Federico
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the VoR from the journal website shown below when it is published
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To be cited as: ChemMedChem 10.1002/cmdc.201800778
Link to VoR: http://dx.doi.org/10.1002/cmdc.201800778
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10.1002/cmdc.201800778
ChemMedChem
COMMUNICATION
A Triazolotriazine-based Dual GSK-3β/CK-1δ Ligand as a
Potential Neuroprotective Agent Presenting Two Different
Mechanisms of Enzymatic Inhibition
Sara Redenti,[a] Irene Marcovich,[a] Teresa De Vita,[b] Concepción Pérez,[c] Rita De Zorzi,[a] Nicola
Demitri,[d] Daniel I. Perez,[c] Giovanni Bottegoni,[e] Paola Bisignano,[f] Maicol Bissaro,[g] Stefano Moro,[g]
Ana Martinez,[c] Paola Storici,[d] Giampiero Spalluto,[a] Andrea Cavalli,*[b] Stephanie Federico* [a]
[a]
Dr S Redenti, I Marcovich, Dr R De Zorzi, Prof G Spalluto, Dr S Federico
Department of Chemical and Pharmaceutical Sciences, University of Trieste
Via Licio Giorgeri 1, 34127 Trieste, Italy
E-mail: sfederico@units.it
[b]
Dr T De Vita, Prof A Cavalli
Drug Discovery & Development (D3), Istituto Italiano di Tecnologia
Via Morego 30, 16163 Genova, Italy
E-mail: andrea.cavalli@iit.it
[c]
[d]
[e]
Dr C Perez, Dr D I. Perez, Prof A Martinez
Centro de Investigaciones Biologicas, CSIC
Avenida Ramiro de Maeztu 9, 28040 Madrid, Spain
Dr P Storici, Dr N Demitri
Elettra - Sincrotrone Trieste S.C.p.A.
SS 14 - km 163,5 AREA Science Park, 34149 Trieste, Italy
Dr G Bottegoni
School of Pharmacy – Institute of Clinical Sciences, College of Medical and Dental Sciences, Sir Robert Aitken Institute for Medical Research, University of
Birmingham
Edgbaston B15 2TT, United Kingdom
[f]
Dr P Bisignano
Cardiovascular Research Institute, University of California San Francisco, United States of America
555 Mission Bay Blvd South, 94158 San Francisco CA
[g]
M Bissaro, Prof S Moro
Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padova
Via Marzolo 5, 35131 Padova, Italy
Supporting information for this article is given via a link at the end of the document.
Abstract: GSK-3β and CK-1δ are emerging targets for the treatment
of neuroinflammatory disorders, including Parkinson’s disease. An
inhibitor able to target these two kinases was developed by docking-
based design. Compound 12, 3-(7-amino-5-(cyclohexylamino)-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide, showed a
combined inhibitory activity against GSK-3β and CK-1δ [IC50(GSK-
3)= 0.17 M; IC50(CK-1)= 0.68 M]. In particular, a classical ATP
competition was observed against CK-1δ, and a co-crystal of
compound 12 inside GSK-3β confirmed a covalent interaction
between cyanoacrylamide warhead and Cys199, which could help in
the development of more potent covalent inhibitors towards GSK-3.
Preliminary studies on in vitro models of Parkinson’s disease
revealed that compound 12 is not cytotoxic, and shows
neuroprotective activity. These results encourage further
investigations to validate GSK-3β/CK-1δ inhibition as a possible new
strategy to treat neuro-inflammatory/degenerative diseases.
that GSK-3β is implicated in microglial-mediated inflammation.[2]
Additionally, CK-1δ is also involved in the neuroinflammatory
process, mainly due to its role in the Wnt and Hedgehog
pathways.[3] Furthermore, GSK-3β and CK-1δ are responsible for
the phosphorylation of proteins that are abundant in the LB,
including tau, α-synuclein, and parkin.[4] The hyper-
phosphorylation of these proteins is responsible for their
aggregation in LB.[5]
These observations suggest that dual GSK-3β/CK-1δ inhibition
could be an interesting multi-target strategy to treat
neuroinflammatory and neurodegenerative diseases such as
PD.[6] For these reasons, we decided to use the versatile
adenine-like [1,2,4]triazolo[1,5-a][1,3,5]triazine (TT) nucleus to
begin synthesizing new inhibitors.[7] In particular, in compounds
1-6, a few amino-substitutions were inserted at the 7 and 5
positions.[8,9] GSK-3 inhibition was displayed by the 5,7-
dicyclohexylamino derivative 4 [IC50(GSK-3)= 5.02 M] (Table
1). Unfortunately, no affinity was detected towards the other
target enzyme, CK-1. We therefore introduced the 3-
amidophenyl moiety at the 2 position of the TT scaffold.[10] This
decision was inspired by the potent CK-1 inhibitor D4476 (7,
Table 1), and based on previous findings (data not shown) that
meta substitutions are preferred. Compounds 8 and 9 showed
promising IC50 values towards CK-1 [8, IC50(CK-1)= 2.59 M; 9,
IC50(CK-1)= 4.28 M] (Table 1), but they were inactive against
the other kinase. We hypothesized a similar pose between ATP
Parkinson’s disease (PD) is the second most common
neurodegenerative disorder after Alzheimer’s disease. The main
pathological hallmarks of PD are the loss of dopaminergic
neurons and the presence of eosinophilic inclusions, called
Lewy bodies (LB), in the substantia nigra pars compacta of the
midbrain.[1] These abnormalities are the result of a complex
pathological
mitochondrial
process
dysfunction,
that
includes
protein
oxidative
aggregation,
stress,
and
neuroinflammation. In recent years, many authors have reported
1
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10.1002/cmdc.201800778
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COMMUNICATION
and TT in the binding pocket of GSK-3. We therefore wondered
if a focused substitution at the 2-position of the TT would target
the non-catalytic cysteine 199 (Cys199), leading to covalent
inhibition of GSK-3, and thus to improved potency towards the
target. In recent years, there has been a resurgence of interest
in covalent inhibitors,[11] and the 2-cyanoacrylamide group can
give a reversible thia-Michael reaction, minimizing the chance of
irreversible modifications of off-target peptides.[12] For these
reasons, we designed the 3-(7-amino-5-(cyclohexylamino)-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)-2-cyanoacrylamide
derivative (12) with an amido moiety to confer potency towards
CK-1.
GSK-3β, while an unreactive isoleucine was present at the same
position in CK-1.
Based on these observations, 12 and its derivatives (13-15)
were synthesized. As reported in Table 2, introducing the
cyanoacrylamide moiety substantially improved the affinity
towards both GSK-3 and CK-1, improving IC50 values to the
sub-micromolar range [12, IC50(GSK-3)= 0.17 M; IC50(CK-1)=
0.68 M]. The combined GSK-3/CK-1 inhibitory activities
suggested 12 to be one of the first examples of a dual GSK-
3/CK-1 inhibitor. To assess 12’s ability to reach the CNS, we
conducted
a
PAMPA-BBB (parallel artificial membrane
permeation assay-blood brain barrier) test. This test showed a
permeability of 1.34 10-6 cm s-1 (Table 2, S3 and Figure S2),
which is close to the limit of passively BBB-permeating
compounds (1.29 10-6 cm s-1). This result was expected due to
the high polar moieties in the molecule, in fact, its predicted logP
value is 0.99. Even if in silico predicted pharmacokinetic
properties are quite good for compound 12 (Table S4), the poor
results in terms of BBB permeability suggest structural
optimization in order to increase the chance of compound to
reach the SNC. In addition, selectivity of compound 12 was
determined against a small panel of related kinases (CDK-2,
CDK-5, CK-1α1, CK-1γ1-3, CK-1ε, CK-2α1) where it results
inactive at a concentration of 10 μM (Table S7).
Table 1. Inhibitory activity of compounds 1-11 against GSK-3 and CK-1
GSK-3
IC50 μM
> 10
CK-1
IC50 μM
> 40
cmpd
R1
R2
R3
1[a]
H
H
H
2
H
cC6H11
H
H
> 10
> 40
3
cC6H11
H
> 10
> 40
To demonstrate the covalent interaction with Cys199 of
GSK-3, we used UV-spectroscopy and HPLC-MS to analyze
the reaction of 12 with the model thiol -mercaptoethanol (BME)
(Figure S3, S5). As expected, results demonstrated the
formation of the 12-BME adduct.[12a] Compound 12’s binding
mechanism was confirmed through substrate competition
experiments on both kinases. These experiments showed an
ATP-competitive inhibition mechanism against CK-1, and a
mixed ATP-competitive/non-ATP-competitive behaviour against
GSK-3 (Figure S6). Moreover, the percentage of GSK-3
inhibition slightly increased with the increased inhibitor exposure
time, confirming that a covalent interaction took place (Figure
S8).
4[b]
cC6H11
cC6H11
Bn
H
5.0 ± 0.3
> 10
> 40
5
H
H
-
H
> 40
6
Ph
H
> 10
> 40
0.3[c]
7, D4476
-
-
-
8
H
H
H
H
cC6H11
CH2Ph
cC6H11
CH2Ph
Ph(3-CONH2)
Ph(3-CONH2)
Ph(3-CN)
Ph(3-CN)
> 10
2.6 ± 0.8
4.3 ± 1.2
>40
9
> 10
10
> 10
11
> 10
>40
[a] already reported by Valbusa et al. and Dolzhenko et al.[8]; [b] already
reported by Akaoshi et al.[9]; [c] data from reference [10]. IC50 data represent
the mean ± SD of 3 independent experiments performed in triplicate. > 10 and
> 40 indicates that two independent experiments in duplicate were performed
at that concentration and the percentage of enzyme activity was more than
50% respect to control.
Table 2. Inhibitory activity of compounds 12-15 against GSK-3 and CK-1
and PAMPA-BBB results of compounds 12 and 15.
GSK-3
IC50 μM
0.17 ± 0.02
> 10
CK-1
IC50 μM
0.68 ± 0.03
> 10
Pe[a]
10-6 cm s-1
1.34
cmpd R1
R2
pred. [a]
12
H
CONH2
CONH2
H
CNS+/-
Figure 1. A) Compound 12 docked in the ATP-binding pocket of CK1-δ (PDB
code: 4HNF). The red arrow indicates the residue Ile148, unsuitable to form
covalent interactions. B) Compound 12 docked in the ATP-binding pocket of
GSK-3β (PDB code: 1Q5K). The red arrow indicates the residue Cys199,
available to form a covalent interaction. In both panels, the key residues of the
binding pocket are reported in light grey x-sticks and labelled explicitly;
hydrogen bond interactions are highlighted by dotted lines.
13
cC6H11
-
-
-
14
15[b]
H
H
> 10
> 10
-
H
5.7 ± 0.2
> 10
2.35
CNS+/-
[a] Permeability (Pe) in the PAMPA-BBB assay of selected compounds with
their predictive penetration in the CNS. [b] trans isomer. IC50 data represent
the mean ± SD of 3 independent experiments performed in triplicate. > 10
indicates that two independent experiments in duplicate were performed at
that concentration and the percentage of enzyme activity was more than 50%
respect to control.
Compound 12 underwent molecular docking studies on both
GSK-3β and CK-1δ (Figure 1). Compound 12 showed an ATP-
competitive binding pose, interacting with residues at both the
Hinge and phosphate regions. Interestingly, the substituent at
the 2-position was oriented towards the nucleophilic Cys199 in
2
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X-ray crystallographic studies confirmed 12 to be a covalent
inhibitor of GSK-3β (Figure S9). An electron density was clearly
observed between the alfa carbon of the cyanoacrylamide group
and the sulfur of Cys199 (Figure 2). The Michael reaction leads
to the formation of two new stereocenters on the compound-
12/Cys-199 adduct. The X-ray structure allowed us to determine
the stereo configuration at both carbons (R,R) of the Michael
addition. This finding allows as to state that, in our case, GSK-3β
have catalysed merely the syn addition on the cyanoacrylamido
group of compound 12. Further investigations are needed to
elucidate the catalytic mechanism that underlies this reaction.
We then assessed the neuroprotective potential of 12’s
GSK-3/CK-1 inhibition in in vitro models of PD, using rat PC12
pheochromocytoma cells in the presence of neurotoxins (4-
phenyl-1-methyl-1,2,3,6-tetrahydropyridine
(MPTP)
or
6-
hydroxydopamine (6-OHDA)).[13] In this cell line, 12 displayed no
cytotoxicity up to a 10 μM concentration (Figure 3A). It also
prevented neurotoxin-induced cell death in a concentration-
dependent manner (Figure 3C and S11).
A
P-Ser9-GSK-3β
total-GSK-3β
1.5
1.0
0.5
0.0
###
##
***
____________ ____________
[cmpd 12] / µM
[LiCl] / mM
_____________________________
Figure 2. X-Ray structure of compound 12 covalently bound in the ATP-
binding pocket of GSK-3β at a resolution of 2.3 Å (PDB code: 6H0U). The
electron density attributed to compound 12 is depicted as a cyan mesh map (σ
level: 1.0); protein secondary structure is depicted as green cartoon, while
residues forming the binding pocket are highlighted as grey sticks; inhibitor is
represented as a ball-and-stick model.
6-OHDA 100 µM
B
β-Catenin
GAPDH
B
A
1.5
1.0
0.5
0.0
125
100
75
50
25
0
125
100
75
50
25
0
#
***
***
***
***
***
_________________
[6-OHDA] / µM
___________
[cmpd 12] / µM
___________ ___________
C
D
[cmpd 12] / µM
[LiCl] / mM
_____________________________
125
100
75
50
25
0
125
100
75
50
25
0
6-OHDA 100 µM
###
###
##
###
#
Figure 4 A) 6-OHDA decreases the level of phospho-Ser9 GSK3β.
***
***
Compound 12 and LiCl counteract this effect. P-Ser9-GSK3β was normalized
to total GSK3β. B) Compound 12 reversed the downregulation of β-Catenin
induced by 6-OHDA. LiCl is used as a positive control. GAPDH protein levels
were used as loading control. Data represent mean ± s.e.m. (n=3). ***p<0.001
vs CTRL, #p<0.1, ##p<0.01, ###p<0.001, §§p<0.01, §§§p<0.001 vs 6-OHDA.
One-way ANOVA followed by Newman-Keuls test.
__________
__________
[cmpd 12] / µM
[LiCl] / nM
_____________
_____________
6-OHDA 100 µM
6-OHDA 100 µM
Figure 3. A) Compound 12 did not affect PC12 cell viability. B) Dose-
dependency of 6-OHDA toxicity in PC12 cells. C-D) PC12 cells were
pretreated with increased concentration of 12 or LiCl and then with 6-OHDA.
Data represent mean ± s.e.m. (n=3). ***p<0.001 vs CTRL, #p<0.1, ##p<0.01,
###p<0.001 vs 6-OHDA. One-way ANOVA followed by Newman-Keuls test.
Recent studies reported compelling evidence for a linkage
between Wnt/-catenin signaling and inflammatory events during
PD progression. Moreover, it is widely recognized that kinase
upregulation,
including
GSK-3,
leads
to
-catenin
degradation.[14] We therefore analyzed the influence of 6-OHDA
3
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[6]
[7]
A. Cavalli, M. L. Bolognesi, A. Minarini, M. Rosini, V. Tumiatti, M.
Recanatini, C. Melchiorre, J. Med. Chem. 2008, 51, 347.
on GSK-3 activity and -catenin expression (Figure 4). Results
showed that, at 100 µM, 6-OHDA decreased the level of
phospho-Ser9 GSK3β. This suggests that 6-OHDA increased
the activity of GSK3β. Compound 12 prevented 6-OHDA-
induced cell death by inhibiting GSK3β (Figure 4A). It also
promoted β-catenin stabilization (Figure 4B), thus restoring its
neuroprotective potential.
In conclusion, we have reported the characterization of a
new [1,2,4]triazolo[1,5-a][1,3,5]triazine derivative. Compound 12
is the first dualGSK-3β/CK-1 inhibitor ever reported, and it
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behaves with two different
(covalent/reversible). X-ray structure revealing
mechanisms of action
covalent
a
interaction between a ligand and Cys199 of GSK-3β is here
reported for the first time. In vitro experiments demonstrated that
12 is fairly effective in protecting neuronal-like cells from
damage, which suggests further studies to evaluate inhibition of
GSK-3β and CK-1 as a strategy for treating neurodegenerative
diseases, such as PD, and neuroinflammatory disorders. In
addition, the obtained crystal structure could help the design and
development of new potent covalent inhibitors towards GSK-3β
using compound 12 as a lead compound.
F. Akahoshi, S. Takeda, T. Okada, M. Kajii, H. Nishimura, M. Sugiura,
Y. Inoue, C. Fukaya, Y. Naito, T. Imagawa, N. Nakamura, J. Med.
Chem.. 1998, 41 (16), 2985.
[10] G. Rena, J. Bain, M. Elliott, P. Cohen, EMBO Rep. 2004, 5 (1), 60.
[11] T. A. Baillie, Angew. Chem. Int. Ed. 2016, 55, 13408.
[12] a) I. M. Serafimova, M. Pufall, S. Krishnan, K. Duda, M. S. Cohen, R. L.
Maglathlin, J.M. McFarland, R. M. Miller, M. Frödin, J. Taunton, Nat.
Chem. Biol. 2012, 8 (5), 471; b) S. Krishnan, R. M. Miller, B. Tian, R. D.
Mullins, M. P. Jacobson, J. Taunton, J. Am. Chem. Soc. 2014, 136,
12624; c) R. M. Miller, J. Taunton, Methods Enzymol. 2014, 548, 93.
[13] a) Z. Arraf, T. Amit, M. B. H. Youdim, R. Farah, Neurosci. Lett. 2012,
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[14] a) M. Golpich, E. Amini, F. Hemmati, N. M. Ibrahim, B. Rahmani, Z.
Mohamed, A. A. Raymond, L. Dargahi, R. Ghasemi, A. Ahmadiani,
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Tirolo, N. Testa, S. Caniglia, M. C. Morale, S. Pluchino, B. Marchetti,
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Acknowledgements
This work was supported by MIUR (PRIN2010W4779), UniTS
(FRA2013), MEIC (SAF2012_37979_CO3_01 and SAF2016-
76693-R). We thank Dr. Barbara Giabbai (Protein Facility -
Elettra Sincrotrone Trieste S.C.p.A.) for her help in protein
cloning, cloning expression, and purification and crystallization
and Eleonora Giacomelli for her help in the synthesis.
Keywords: glycogen synthase kinase 3 beta • casein kinase 1
delta • Parkinson’s disease • neuroinflammation • thia-Michael
reaction
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4
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Entry for the Table of Contents
A dual inhibitor of GSK-3β and CK-1δ kinases was discovered. Compound 12 is an ATP competitive inhibitor of CK-1δ, and a
covalent inhibitor of GSK-3β. It showed neuroprotective activity in vitro preliminary tests, suggesting further investigations to validate
this dual inhibition as a promising strategy for treating neuroinflammatory disorders, such as Parkinson’s disease.
5
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