Developing DYRK inhibitors derived from the meridianins as a means of increasing levels of NFAT in the nucleus

Article abstract of DOI:10.1016/j.bmcl.2017.03.037

A structure-activity relationship has been developed around the meridianin scaffold for inhibition of Dyrk1a. The compounds have been focussed on the inhibition of kinase Dyrk1a, as a means to retain the transcription factor NFAT in the nucleus. NFAT is responsible for up-regulation of genes responsible for the induction of a slow, oxidative skeletal muscle phenotype, which may be an effective treatment for diseases where exercise capacity is compromised. The SAR showed that while strong Dyrk1a binding was possible with the meridianin scaffold the compounds have no effect on NFAT localisation, however, by moving from the indole to a 6-azaindole scaffold both potent Dyrk1a binding and increased NFAT residence time in the nucleus were obtained – properties not observed with the reported Dyrk1a inhibitors. One compound was shown to be effective in an ex vivo muscle fiber assay. The increased biological activity is thought to arise from the added interaction between the azaindole nitrogen and the lysine residue in the back pocket.

Full text of DOI:10.1016/j.bmcl.2017.03.037

Accepted Manuscript
Developing DYRK inhibitors derived from the meridianins as a means of in-
creasing levels of NFAT in the nucleus
Simon J. Shaw, Dane A. Goff, Nan Lin, Rajinder Singh, Wei Li, John
McLaughlin, Kristen A. Baltgalvis, Donald G. Payan, Todd M. Kinsella
PII:
S0960-894X(17)30268-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.03.037
BMCL 24789
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 February 2017
14 March 2017
15 March 2017
Please cite this article as: Shaw, S.J., Goff, D.A., Lin, N., Singh, R., Li, W., McLaughlin, J., Baltgalvis, K.A., Payan,
D.G., Kinsella, T.M., Developing DYRK inhibitors derived from the meridianins as a means of increasing levels
of NFAT in the nucleus, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.
2017.03.037
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Developing DYRK inhibitors derived from
meridianins as a means of increasing levels
of NFAT in the nucleus
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Simon J. Shaw*, Dane A. Goff, Nan Lin, Rajinder Singh, Wei Li, John McLaughlin, Kristen A. Baltgalvis,
Donald G. Payan, Todd M. Kinsella

Bioorganic & Medicinal Chemistry Letters
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Developing DYRK inhibitors derived from the meridianins as a means of
increasing levels of NFAT in the nucleus
Simon J. Shaw*, Dane A. Goff, Nan Lin, Rajinder Singh, Wei Li, John McLaughlin, Kristen A. Baltgalvis,
Donald G. Payan, Todd M. Kinsella
Rigel Pharmaceuticals, Inc., 1180, Veterans Boulevard, South San Francisco, California 94080, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
A structure-activity relationship has been developed around the meridianin scaffold for
inhibition of Dyrk1a. The compounds have been focussed on the the inhibition of kinase
Dyrk1a, as a means to retain the transcription factor NFAT in the nucleus. NFAT is responsible
for up-regulation of genes responsible for the induction of a slow, oxidative skeletal muscle
phenotype, which may be an effective treatment for diseases where exercise capacity is
compromised. The SAR showed that while strong Dyrk1a binding was possible with the
meridianin scaffold the compounds have no effect on NFAT localisation, however, by moving
from the indole to a 6-azaindole scaffold both potent Dyrk1a binding and increased NFAT
residence time in the nucleus were obtained - properties not observed with the reported Dyrk1a
inhibitors. One compound was shown to be effective in an ex vivo muscle fiber assay. The
increased biological activity is thought to arise from the added interaction between the azaindole
nitrogen and the lysine residue in the back pocket.
Revised
Accepted
Available online
Keywords:
Dyrk1a
Meridianin
NFAT
Duchenne muscular dystrophy
6-azaindole
2015 Elsevier Ltd. All rights reserved.
Dual-specificity Tyrosine-regulated Kinase (Dyrk) belongs to
the CMGC family of kinases, which includes the Glycogen
Synthase Kinase 3β (GSK3β), Casein Kinase 2 (CK2), Cyclin
Dependent Kinases (CDKs) and Mitogen-Activated Protein
Kinase (MAPK). The Dyrk family consists of five members in
two classes – class 1 (1a and 1b) and class 2 (2, 3 and 4). Dyrk1a
is found on chromosome 21, and is responsible for some of the
phenotypes found in Down’s Syndrome patients, including
growth abnormalities.1-3 Further, Dyrk1a has been shown to
phosphorylate Tau and has been implicated in Alzheimer’s
disease,4-6 indeed symptoms of Alzheimer’s occur earlier in
patients with Down’s Syndrome than the general population.
While there is a clear need for intervention in these situations we
were intrigued by an additional role of Dyrk1a – as a priming
kinase for the inactivation of nuclear factor of activated T-cells
(NFAT).7
models with the compound SMT C1100, a utrophin up-regulator,
in clinical trials for Duchenne muscular dystrophy.10 We
believed that inhibition of Dyrk1a would increase the residence
of NFAT in the nucleus resulting in increased transcription of
utrophin A.
Harmine 1 (Figure 1) is often used as the archetypical Dyrk1a
inhibitor. However, in recent years, several classes of Dyrk1a
inhibitors have been reported (INDY,11 V-shaped molecules,12
leucettines,13 lamellarin D analogues,14 a series of pyrimidines,15
and azaindoles16), including a series derived from the meridianin
natural products.17, 18 The meridianins, isolated from the tunicate
Aplidium meridianum, are marine alkaloids characterized by an
indole ring connected to a pyrimidine at the three position e.g.
meridianin G, 2. Meridianins bind in the ATP binding pocket
through a hinge contact between the pyrimidine N-1 and the 2-
amino group of the pyrimidine, while the indole sits in the back
pocket, with the potential to form a π-π interaction with the
phenylalanine gatekeeper. Derived from meridianins there have
been N-1-substituted derivatives19 reported as well as the
analogous 6-azaindole scaffold reported by Kettle et al,20 which
resulted in 3, a compound designed for selective Dyrk1b
inhibition. These results have prompted us to report our own
initial efforts to investigate meridianin derivatives as Dyrk1a
inhibitors, which were able to increase residence time of NFAT
in the nucleus as an initial step in increasing utrophin A levels.
NFAT is a transcription factor with several roles including
the switch from fast twitch to slow twitch muscle fibre8 and the
up-regulation of utrophin through interaction with the utrophin A
promoter.9 After phosphorylation by Dyrk1a, NFAT is further
phosphorylated by GSK3β and CK1, resulting in its removal
from the nucleus and thus inactivation.
Increasing levels of utrophin has been proposed as a possible
therapeutic in muscular dystrophy, since it has been shown that
utrophin can serve as a functional replacement for dystrophin.
Indeed this approach has shown to be successful in animal

Table 1. Meridianin derivatives synthesized and their binding
activities and ability to translocate NFAT
Binding IC50 (µM)a
NFAT
(µM)
Compound
R1
R2
Dyrk1a
GSK3β
IAc
1, Harmine
0.041
NDc
ND
IA
2, Meridianin G
0.588 (0.700)b
0.019
14.81
IA
Figure 1. Structures of Dyrk inhibitors.
3
H
We began our studies by investigating the meridianin indole
scaffold. In particular, analysis of the docking suggested that the
hinge binding was effected by the pyrimidine N-1 and the amino
group at the 2-position with no contribution from the pyrimidine
N-3.21 To investigate this hypothesis, a series of compounds
were generated with the 2-aminopyrimidine and the
corresponding 2-aminopyridine at the 3-position of the indole
ring (Scheme 1, Table 1). Compounds were synthesized by
iodination of the indole to generate 5 followed by N-tosylation to
6. A one-pot two-step protocol developed by Müller22 (Masuda
borylation followed by Suzuki coupling 6 to 7 to 8) followed by
removal of the tosyl group resulted in the pyrimidine derivatives
8a-h. The pyridine derivatives 9b-h were generated through
Suzuki coupling between the 3-iodoindole 6 and 2-aminopyrine-
4-boronic acid, with in situ deprotection of the tosyl group.
8a
8b
9b
8c
9c
8d
9d
8e
9e
8f
Br
NO2
NO2
Cl
0.079 (0.068)b
(0.085)b
0.285
22.45
9.95
IA
ND
ND
IA
H
H
H
0.046
IA
IA
H
Cl
0.094
IA
IA
Cl
H
0.406
10.69
IA
ND
ND
9.8
ND
ND
ND
21.7
IA
Cl
H
2.939
H
OMe
OMe
H
0.242
15.84
IA
H
2.142
OMe
OMe
H
0.443
7.96
12.70
5.16
13.86
15.29
IA
9f
H
2.904
8g
9g
8h
9h
CN
CN
H
0.138
H
0.790
CF3
CF3
0.062
ND
ND
H
4.335
a Invitrogen LanthaScreenTM Eu Kinase Binding Assay
(www.thermofisher.com); b from reference 15; c IA –inactive, ND – not
determined
Our binding data for the literature compounds (1-3) are
consistent with that reported (compound 3 IC50 for Dyrk1b 0.007
µM).
However, although the 3-position nitrogen in the
pyrimidine ring does not appear to be necessary for binding to
Dyrk1a in the docking studies, the aminopyridine compounds 9b-
h are consistently significantly weaker in the binding assay than
the analogous aminopyrimidines 8a-h (Table 1). The exception
is the 7-chloroindole 9c, which does show good binding although
weaker than the corresponding aminopyrimidine 8c (0.094 µM
vs. 0.046 µM). Further comparison of the 6-substituted
compounds relative to the corresponding 7-substituted analogues
(e.g. 8c vs 8d and 8e vs 8f) shows the 7-substitution to be
superior. All the compounds show good selectivity for Dyrk1a
over GSK3β (8f being the lowest at 18-fold). The most potent
Dyrk1a binders (8c, 9c, 7h) did not show any activity in our
translocation assay.
In the translocation assay itself we transfected cells with green
fluorescent protein (GFP) tagged NFAT and analyzed for GFP in
the nucleus. The NFAT number refers to the concentration
required to maintain 50% of the GFP-tagged NFAT in the
nucleus after a three-hour treatment. It was shown that electrical
stimulation of the cells resulted in GFP-tagged NFAT going into
the nucleus and subsequently dissipating over approximately 30
minutes. However, for the experiments described in this
manuscript there was no stimulation used apart from the
compound itself. Ionomycin is used as a positive control for the
assay, which is described more fully in the Supplementary
Material.
Scheme 1. Upper - Synthesis of meridianin and pyridine analogues.
Reagents and conditions (a) NIS, CH3CN, rt, 2h (b) NaH, DMF, 0°C, 1h,
TsCl, 0°C, 3h (c) pinacol borane, Pd(PPh3)4, dioxane, 80°C, 3h, cool to rt, (d)
MeOH, 4-chloro-2-aminopyrimidine, Cs2CO3, 100°C, 14h (e) 2-
aminopyridine-4-boronic acid, K3PO4, Pd(PPh3)4, n-butanol, H2O, 140°C, 1h.
Lower - A pose of compound 8a docked to DYRK1a.
It was considered that the compounds might show improved
potency in the NFAT translocation assay if we could increase the
number of binding interactions of the molecules in the binding
pocket. Moving from the indole to the 6-azaindole scaffold was

considered to be one method of effecting such an increase in
binding by allowing for an interaction between the 6-nitrogen of
the azaindole with the back-pocket lysine-188 of the Dyrk1a
protein.
Synthesis of the 6-azaindole meridianin analogue 10 was
carried out from 6-azaindole 11 using a route reported in the
patent literature,23 that is to say iodination and N-1 protection to
form 12. A Sonogashira reaction was used to introduce a
hydroxymethylacetylene, which was oxidized to the ynal 13.
Reaction of ynal 13 with guanidine hydrochloride resulted in the
aminopyrimidine 10. The pyridine analogues 14-21 could be
obtained from 12 through Suzuki reaction (Scheme 2).
A further series of N-alkyl compounds 22-27 of 3-(4-pyridyl)-
6-azaindole 14 were synthesized through a Mitsunobu protocol.
In carrying out this reaction a more polar compound was also
obtained, which was believed to be the regioisomer in which the
alkyl group was located at the 6-position of the azaindole
(Scheme 2). These regioisomeric compounds were not able to
bind Dyrk1a and as such were not active in the NFAT
translocation assay. The result is consistent with the docking
pose for 14, which shows that the nitrogen in the 6-position of
the azaindole makes an interaction with the lysine-188 in the
back pocket of the ATP binding site. It is noteworthy that the
docking suggests that there is little space for substitution around
the pyridine ring of the azaindole (Figure 2).
Scheme 2. Synthesis of 6-azaindole meridianin analogues. Reagents and
conditions (a) NIS, CH3CN, rt 1.5h (b) NaH, DMF, 0°C, 30 min, PhSO2Cl,
0°C, 3h (c) HCCCH2OH, Pd(PPh3)4, CuI, dioxane, 100°C, 14h (d) Dess-
Martin periodane, CH2Cl2, rt, 20 min (e) guanidine.HCl, MeOCH2CH2OH,
80°C, 10h (f) ArB(OH)2, Na2CO3, Pd(PPh3)4, dioxane, H2O, 130°C, 1h,
µwave (g) NaOMe, MeOH, 100°C, 45 min (h) ROH, PPh3, DIAD, THF, 0°C,
2h then rt, 14h
Figure 2. Docking of compound 14 into the Dyrk1a ATP binding site.
The 6-azaindole compounds were screened for their ability to
bind both Dyrk1a and GSK3β along with their ability to
translocate NFAT into the nucleus in human primary myotubes
(Table 2). The results showed that the introduction of a binding
interaction in the back pocket of the ATP binding site does
increase the binding potency without impact on the selectivity
relative to GSK3β. Further, the more potent Dyrk1a inhibitors
were able to effect translocation of NFAT into the nucleus. For
example, the 2-aminopyrimidin-4-yl compound 10 shows 1 nM
binding potency to Dyrk1a and the increase in binding results in
an improvement in NFAT translocation. More strikingly, the 4-
pyridyl compound 14 shows similar 1 nM binding to Dyrk1a.
Again the compound is able to translocate NFAT in cells.
Moving from a 4-pyridyl to the 3-pyridyl (14 vs. 15) results in a
significant drop in binding which is assumed to be due to the
ineffective interaction with the hinge in the case of 15, showing
that both the hinge interaction and the lysine back-pocket
interaction are important for effective binding. Substitution of
the pyridine ring ortho to the pyridine nitrogen ring results in a
reduction in binding potency (e.g. 14 vs. 16, 17, 21). The 2-
methylpyridine 18 and 2-fluoropyridine 19 binding to Dyrk1a in
the 70 nM range, with 19 able to translocate NFAT in cells. The

synthetically more challenging Suzuki coupling with substitution
of the pyridine at the meta position as in the 3-chloropyridyl
compound 20 also results in reasonable potency.
25 at 10 µM
DMSO
Table 2. Biological data for 6-azaindole compounds.
Binding IC50 (µM)
Compound
NFAT
(µM)
Dyrk1a
0.001
0.001
7.957
2.024
0.351
0.075
0.069
0.061
0.277
0.089
0.008
0.010
0.008
0.109
0.012
GSK3β
12.30
9.23
31.01
IA
10
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4.80
2.98
IA
IA
IA
IA
IA
20.82
4.85
5.31
42.98
2.21
1.59
6.90
0.31
6.96
7.58
IA
9.61
IA
4.78
1.14
3.00
0.66
7.58
1.01
Figure 3. The image shows the comparison of dosing of compound 25 at
10 µM to DMSO for the location of GFP-NFAT in the top pane and DAPI
staining for the nucleus in the lower pane.
In summary we have described a series of meridianin derived
6-azaindole inhibitors of Dyrk1a, which are able to increase the
residence time of the transcription factor NFAT within the
nucleus. Key to the NFAT activity in cells was the use of the 6-
azaindole scaffold, which allows for a binding interaction in the
back pocket of the kinase between the 6-position nitrogen and
Lys-188 of Dyrk1a. The compounds have demonstrated greater
than 10-fold selectivity for Dyrk1a over GSK3β a fellow GMCG
family member. In addition the most potent compound was
shown to be active in an ex vivo muscle fiber assay. The effect
on NFAT has not been reported previously for Dyrk inhibitors,
and is an effect we observe only weakly with the reported
meridianin-derived compounds. While the translocation assay
tracks with the binding assay in terms of the order of potency
reasonably well, there remains a difference in sensitivity between
the two assays - the most potent nanomolar binders of Dyrk1a
show micromolar potency in the translocation assay. In addition
to the limitations of isolated kinase assays to mimic the cell
environment, we note that the translocation of NFAT into the
nucleus is a complex dynamic process. It involves the action of
kinases and phosphatases as well as proteins required for the
import and export of NFAT into and from the nucleus, which
may be responsible for the differences between the two assays.
Current studies are aimed at identifying compounds with suitable
PK properties for animal models, which may be able to switch
muscle fibers from fast- to slow-twitch and potentially have an
effect on utrophin levels.
The addition of an N-1 substituent does not improve Dyrk1a
binding; however an improvement in NFAT translocation is
observed in several cases (compounds 22, 23 and 25), with the N-
isopropyl compound 25 showing submicromolar potency. The
more polar N-morpholinoethyl 26 shows weaker binding and
poor NFAT translocation suggesting
a
preference for
hydrophobic groups. While 25 and 27 show reduced binding
selectivity for Dyrk1a over GSK3β, both maintain a selectivity
ratio of greater than 10-fold. We believe that for these
compounds Dyrk1a inhibition is the main driver of potency in the
NFAT translocation assay.
It is interesting to note that
compound 3 was inactive in the NFAT translocation assay
despite having the same 6-azaindole as the compounds presented
in Table 2 and binding to Dyrk1a in a similar range, however, the
result is consistent with 27. Both compounds contain a benzylic
N-1 substituent and show poor potency in the NFAT
translocation assay.
The 3-(4-pyridyl)-6-azaindole 14 was screened in a kinase
panel at 10 µM. The compound inhibited both Dyrk1a and
Dyrk1b as expected; however, the compound showed no
significant inhibition (less than 30% inhibition) against any of the
remaining kinases in the panel, including members of the CMGC
kinase family, GSK3β, the CDK’s, casein kinases (CK’s) and
MAP kinases (see Supplementary Material for full details).
Finally an ex vivo experiment was carried out in which
muscle fibers were dissociated from the paw of a mouse and
transfected with GFP-NFAT. The most potent compound in the
cellular assay, the 1-isopropyl-3-(4-pyridyl)-6-azaindole 25,
clearly showed the ability to retain NFAT in the nucleus relative
to the DMSO control - compound treated muscle strips show
more of the GFP concentrated in spots, which correlate to the
nucleus, while in the DMSO treated muscle strip the GFP is
more diffuse (Figure 3 and Supplementary Material). The
compound was determined to have an EC50 of 2.8 µM in this
assay.
Acknowledgments
We thank Mark Irving and Duyane Tokushige for purification
assistance and high-resolution mass spectrum determinations.
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