Synthesis of novel 1H-Pyrazolo[3,4-b]pyridine derivatives as DYRK 1A/1B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2021.128226

As DYRK1A and 1B inhibitors, 1H-pyrazolo[3,4-b]pyridine derivatives were synthesized. Mostly, 3-aryl-5-arylamino compounds (6) and 3,5-diaryl compounds (8 and 9) were prepared and especially, 3,5-diaryl compound 8 and 9 showed excellent DYRK1B inhibitory enzymatic activities with IC₅₀ Values of 3–287 nM. Among them, 3-(4-hydroxyphenyl), 5-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine (8h) exhibited the highest inhibitory enzymatic activity (IC₅₀ = 3 nM) and cell proliferation inhibitory activity (IC₅₀ = 1.6 μM) towards HCT116 colon cancer cells. Also compound 8h has excellent inhibitory activities in patient-derived colon cancer organoids model as well as in 3D spheroid assay model of SW480 and SW620. The docking study supported that we confirmed that compound 8h binds to DYRK1B through various hydrogen bonding interactions and hydrophobic interactions.

Full text of DOI:10.1016/j.bmcl.2021.128226

Bioorg. Med. Chem. Lett. 47 (2021) 128226
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel 1H-Pyrazolo[3,4-b]pyridine derivatives as DYRK 1A/
1
B inhibitors
a
,
b
,
1
d
,
e
,
1
a
c
c,
g
c,g
Areum Park
, Jieon Hwang
, Joo-Youn Lee , Eun Ji Heo , Yoon-Ju Na , Sein Kang
,
b
c
,
g
,
*
e
,
f
,
*
a,c,*
Kyu-Sung Jeong , Ki Young Kim
, Sang Joon Shin
, Hyuk Lee
a
Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea
b
c
d
e
f
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea
Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
Drug Discovery Platform Technology Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
g
A R T I C L E I N F O
A B S T R A C T
Keywords:
As DYRK1A and 1B inhibitors, 1H-pyrazolo[3,4-b]pyridine derivatives were synthesized. Mostly, 3-aryl-5-aryla-
mino compounds (6) and 3,5-diaryl compounds (8 and 9) were prepared and especially, 3,5-diaryl compound 8
and 9 showed excellent DYRK1B inhibitory enzymatic activities with IC50 Values of 3–287 nM. Among them, 3-
DYRK1A
DYRK1B
Kinase Inhibitors
Pyrazolopyridines
Colon cancer
Organoid
(
4-hydroxyphenyl), 5-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine (8h) exhibited the highest inhibitory
enzymatic activity (IC50 = 3 nM) and cell proliferation inhibitory activity (IC50 = 1.6 µM) towards HCT116 colon
cancer cells. Also compound 8h has excellent inhibitory activities in patient-derived colon cancer organoids
model as well as in 3D spheroid assay model of SW480 and SW620. The docking study supported that we
confirmed that compound 8h binds to DYRK1B through various hydrogen bonding interactions and hydrophobic
interactions.
DYRK (Dual-specificity tyrosine phosphorylation-regulated kinases)
cells from quiescent state.26,27 In this reason, the development of
DYRK1B inhibitors are mostly concentrated on the treatment of onco-
lytic diseases (Fig. 1).28 So far several DYRK1A and 1B inhibitors have
belongs to CMGC group, which includes cyclin-dependent kinases
(
CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase
2
9
kinases (GSKs) and CDC-like kinases (CLKs). DYRK family is constituted
with DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4.1 DYRK1A is one
entered clinical trials. As DYRK1A inhibitors, Lorecivivint is under-
going phase III trial as treatment of osteoarthritis and
,2
a
of the most studied DYRK family and upregulation of DYRK1A3 in
brain is related with several neurodegenerative diseases including Down
syndrome7 and Alzheimer’s disease.9–11 The relevant diseases with
–6
epgigallocatechin-gallate (EGCG) from green tea is in phase II/III clin-
ical trial for cancer immunotherapy. Besides, many DYRK1A and 1B
inhibitors are under investigation in the preclinical stage with diverse
,8
DYRK1A were expanded to diverse cancers1
2–14
such as lung cancer,
indications. AZ191 has been studied as oncolytic drugs and the GNF-
25
cervical cancer, colorectal cancer, melanoma, and acute myeloid leu-
kemia. Recently, it was reported that DYRK1A is engaged in human
487730 is under development as antidiabetic drug. Harmine31,32 and
ProINDY33 from natural products have been studied for various disease,
and based on their structures, azaindole and benzothiazoylidene other
novel DYRK1 inhibitors have been designed and synthesized. Leucett-
amine L4134 from the marine sponge leucettamine is also under pre-
1
5–19
pancreatic β-cell proliferation,
which led it a potential therapeutic
The DYRK1B is associated with cancer biology
and muscle differentiation, and overexpressed in many types of cancer
target for diabetes.2
0,21
2
2
23
24
35
cells such as glioblastoma, breast cancer, pancreatic cancer, and
ovarian cancer.25 Also DYRK1B contributes to progress cell cycle from
G0/G1 to S phase, therefore, inhibition of DYRK1B reactivates cancer
clinical study for neurodegenerative disease. DANDY is also an
azaindole-based compounds, and recently it is reported that one of
fluoro-DANDY derivatives has cognitive rescuing effect by in vivo study
*
Corresponding authors.
E-mail addresses: kykim@krict.re.kr (K.Y. Kim), ssj338@yuhs.ac (S.J. Shin), leeh@krict.re.kr (H. Lee).
1
These authors contributed equally.
https://doi.org/10.1016/j.bmcl.2021.128226
Received 11 May 2021; Received in revised form 16 June 2021; Accepted 20 June 2021
Available online 26 June 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.

A. Park et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128226
of standard mouse model of Down syndrome.36
Table 1
We are interested in 1H-pyrazolo[3,4-b]pyridine core for developing
novel DYRK inhibitors, which has additional nitrogen in azaindole core.
We believed this core structure could provide improved activities
against DYRK1A/1B and novel characteristics of compound properties.
So we prepared diverse 1H-pyrazolo[3,4-b]pyridine derivatives and
examined the cytotoxicity of them against colorectal cancer cell lines.
From the Commercially available 5-bromo-1H-pyrazolo[3,4-b]pyri-
dine 1, mono-substituted DYRK 1A/1B inhibitors were firstly synthe-
sized. For the modification on the C3 position of compound 1, iodination
Inhibitory enzymatic activities of compounds 4.
1
a,b
Compound
R
DYRK1B IC50 (nM)
2040
4
a
b
4
>5 µM
>5 µM
635
4c
at the C3 position of 1 with I
N-protected by a SEM group with trimethylsilylethoxymethyl chloride
SEMCl) and the following regioselective Suzuki-miyaura cross-coupling
at C3 position with arylboronic acids afforded C3-substituted compound
2
was performed. Then the resulting 2 was
4
4
d
e
(
257
3
a-o in 47–76% yields. Deprotection of SEM group from 3 resulted in
4
4
4
f
54
mono-substituted 4a-o.
With these compounds in hand, inhibitory enzymatic activities of 4a-
o against DYRK1B were examined (Table 1). Staurosporine was used as a
reference compound. Most of phenyl-substituted derivatives (4a-j)
exhibited moderate to excellent inhibitory activities with IC50 values in
the range of 54–2040 nM, except for 3-methoxyphenyl (4b), 3-nitro-
phenyl (4c), and 4-nitrophenyl (4i) substituents which had no inhibi-
tory activity. Especially, 4-methoxyphenyl (4f) and 4-hydroxy (4g)
compounds showed the highest inhibitory activities with IC50 values in
the range of 54 and 87 nM, respectively. When heteroaromatic sub-
stitutes were introduced into 1H-pyrazolo[3,4-b]pyridine, the IC50
values of them (4k-o) against DYRK1B were ranged from 121 to 4,038
nM. We selected four compounds (4e, 4g, 4j, and 4m) to test DYRK1A
inhibitory activities and their IC50 values appeared similar compared to
those against DYRK1B.
g
h
87
1050
4
4
i
j
>5 µM
568
4
4
4
k
l
615
4038
141
m
Next, we synthesized di-substituted 1H-pyrazolo[3,4-b]pyridine de-
rivatives to increase the inhibitory activity against DYRK1B (Scheme 2).
4
n
736
121
Based on compound 3 in Scheme 1, the C
–
N bond coupling of 3 with
4o
arylamines in the presence of Pd dba and Xantphos and the following
2
3
deprotection of SEM group from the corresponding products by TBAF
afforded 3-aryl-5-arylamino-1H-pyrazolo[3,4-b]pyridines (6a-g). In
another way, consecutive Suzuki-miyaura cross-coupling of 3 with
arylboronic acids resulted in N-SEM-protected 3,5-diaryl-1H-pyrazolo
Staurosporine
3
a
IC50 values were determined from concentration-dependent inhibition
curves of triplicate experiments by GraphPad Prism software.
b
[
3,4-b]pyridines (7a-j) in 61–99% yields. Subsequent deprotection of 7
gave rise to diaryl compounds (8a-j). During the process, 4-aminophenyl
compound 7k was followed by the additional reaction with CH SO Cl,
DYRK1A enzymatic activities (IC50) for the selected compounds : 4e (638
nM), 4g (56 nM), 4j (1,107 nM), and 4m (92 nM)
3
2
Fig. 1. DYRK inhibitors and their development status.
2

A. Park et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128226
Table 2
Inhibitory enzymatic activities of compounds 6
2
1
Compound
R
R
DYRK 1A
IC50 (nM)
DYRK 1B
IC50 (nM)
a
a
6a
6b
6c
2817
950
575
191
>5 µM
3683
6
6
d
e
365
33
188
31
2
Scheme 1. Reagents and conditions (a) I (1.1 equiv), KOH (2.1 equiv), DMF,
rt, 2 h, 83%; (b) SEMCl (1.7 equiv), NaH (2.0 equiv), DMF, rt, 2 h, 95%; (c) R-B
OH) (1.1 equiv), Pd(dppf)Cl Cl (5 mol%), 2 M K CO (3.0 equiv),
⋅CH
CH
CN, 85 ℃, 3 h, 47–76%; (d) TBAF (20.0 equiv), THF, reflux, 4 h, 29–99%.
(
2
2
2
2
2
3
6f
309
309
3
6
g
3553
1273
Staurosporine
11
3
a
IC50 values were determined from concentration-dependent inhibition
curves of triplicate experiments by GraphPad Prism software.
Most of diaryl 1H-pyrazolo[3,4-b]pyridine derivatives 8 and 9
showed more improved inhibitory activities against DYRK 1B than
compounds 6a-g, except for 8a with 3,4-diphenyl substituents (Table 3).
With 3,4-dimethoxyphenyl substituent at C5 position, the derivatization
of diverse aryl substituents at C3 position gave rise to the range of IC50
values of 97–287 nM against DYRK 1B (Table 3, 8b-d). When 4-hydrox-
ylphenyl substituent (8e-f) was introduced, the inhibitory activities
were highly increased from IC50 6 to 56 nM. But, 3-hydroxyphenyl
substituent (8g) was not effective as much as 4-hydroxyphenyl substit-
uent. Most compounds with 3,4-hydroxyphenyl group (8h-j) exhibited
the highest inhibitory activities with IC50 values of 3–29 nM. Methyl-
sulfonylamino, acylamino and ureido substituents also increased DYRK
Scheme 2. Reagents and conditions (a) Pd
), Cs CO
(2.0 equiv), 1,4-dioxane, 90 ℃, 12 h, 44–76%; (b) TBAF (20.0
equiv), THF, reflux, 4 h, 31–62%; (c) R-B(OH) (1.1 equiv), Pd(dppf)Cl ‧CH Cl
5 mol%), 2 M K CO (3.0 equiv), CH (10.0
CN, 85 ℃, 3 h, 61–99%; (d) BBr
equiv), DCM, rt, 24 h, 24–74%.
2 3
dba (10 mol%), Xantphos (10 mol
%
2
3
2
2
2
2
(
2
3
3
3
1
B inhibitory activities with IC50 values of 2–13 nM (Table 3, 9a-e). In
terms of DYRK 1A, most results of diaryl 1H-pyrazolo[3,4-b]pyridine
derivatives were comparable to those of DYRK 1B.
2
Ac O, and potassium cyanate (NCOK) to obtain the corresponding
products (9a-e) (Scheme 3).
With the enzymatic activities of DYRK1B inhibitors, the cytotoxic
activities against colon cancer cells (HCT116) were investigated. Firstly,
several compounds (8h, 9a, 9b, 9c, and 9e) were selected and tested.
Among them, compounds 8h, 9a, and 9b showed excellent cell prolif-
When 3-aryl-5-arylamino-1H-pyrazolo[3,4-b]pyridines (6a-g) were
tested for the inhibitory activities of DYRK1B, their IC50 values slightly
improved compared to mono-substituted 4 (Table 2). When compare to
4
b with 4-methoxyphenyl substituent, additional phenylamino (6a), 3-
eration inhibitory activities with IC50 values of 3.4, 1.6, and 2.1
respectively. Rest of compounds 9b and 9c remained with IC50 values of
6.2 and 8.9 M, respectively (see supplementary data Fig. S1). After
μM,
hydroxyphenylamino (6b), and 3-benzyloxyphenylamino (6c) sub-
stituents enhanced DYRK 1B inhibitory activities with IC50 values of 575
nM, 191 nM, and 3,683 nM, respectively. But, extra arylamino sub-
stituents (6d, 6f, and 6g) into 4f remained less effective against
DYRK1B, and only 6e showed similar to 4f. The inhibitory activities of
1
μ
considering their Inhibitory enzymatic, cell proliferation inhibitory ac-
tivities and other chemical properties including solubilities, we decided
to further examine 8h.
6
a-g against DYRK1A are also very similar to those against DYRK 1B.
To figure out the effect of 8h on cytotoxicity towards colon cancer
cells, we measured cell proliferation inhibitory activity in 10 colon
cancer cell lines (RKO, HCT116, DLD-1, SW620, SW480, COLO205,
HT29, LOVO, HCT15, and LS174T). Compound 8h showed remarkable
cytotoxic efficacy against five colon cancer cells such as RKO, HCT116,
DLD-1, SW480 and SW620 and exhibited divergent sensitivity (IC50
values of 1–38 µM) (Fig. 2a). In addition, the morphology of cells
treated with 8h showed multi-vesicle formation compared to vehicle-
treated cells (Fig. 2b). Therefore, we could predict the induction of
autophagy by 8h since they showed the morphologically specific form of
autophagic cell death.
Next, we assessed cell growth inhibitory effect through 3D spheroid
model that the microenvironment of cancer cell was more resembled
that of a patient’s tumor tissues (Fig. 3). At day 10 after the treatment of
Scheme 3. Reagents and conditions. (a) CH
0%; (b) Ac O (1.5 equiv), AcOH, 110 ℃, 5 h, 65%; (c) NCOK (1.2 equiv), 2 N
HCl, 0 ℃ to rt, 6 h, 80%; (d) TBAF (20.0 equiv), THF, reflux, 4 h, 37–67%.
3 2
SO Cl (2.0 equiv), DCM, rt, 12 h,
9
2
8
h, the cell size of SW480 and SW620 was reduced. The number of
3

A. Park et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128226
Table 3
Inhibitory enzymatic activities of diaryl 1H-pyrazolo[3,4-b]pyridine derivatives.
3
1
Compound
R
R
DYRK 1A
IC50 (nM)
DYRK 1B
IC50 (nM)
a,b
a
8
a
b
>5
μM
>5 M
μ
8
75
97
8
8
8
8
c
d
e
f
632
299
44
287
167
56
5
6
8
8
g
213
5
39
3
h
8
8
9
i
24
29
15
5
Fig. 2. Cytotoxicity and cells morphology treated with compound 8h.
j
NT.
NT
a
9
9
9
9
b
c
NT
8
13
7
d
e
NT
NT
11
10
2
Staurosporine
3
a
IC50 values were determined from concentration-dependent inhibition
curves of triplicate experiments by GraphPad Prism software.
b
NT: Not tested.
viable cells stained with calcein AM decreased and the size of nuclei
stained with Hoechst33342 became smaller. In addition, we found that
the number of dead cells stained with ethidium homodimer-1 (EthD-1)
increased (Fig. 3). Therefore, the cytotoxic activity of DYRK1 inhibitor
2
Fig. 3. 3D spheroid assay with compound 8h. Cells (SW480: 1 × 10 per well
3
and SW620: 1x10 per well) were seeded at 96 well U-bottom plate coated with
8
h towards SW480 and SW620 colon cancer cells continued to maintain
poly-HEMA. At 3, 5, 7 days, cells were treated with compound 8h (5 M). Then,
μ
in 3D spheroid models of them.
cells were stained with Hoechst33342 (Nuclei), Calcein AM (Live cell) and
Ethidium Homodimer-1 (Dead cell). Representative images were taken on day
10 at 50Х.
Finally, we verified the cytotoxic effect of 8h in patient derived
cancer organoid models. As shown in Fig. 4, the treatment of 8h
exhibited reduction of crypt size and disruption of intact organoid
structure compared to that of vehicle-treated organoids. Altogether,
DYRK1 inhibitor, 8h, showed prominent cytotoxic effect in colon cancer
cell lines through diverse models.
In conclusion, we successfully designed and synthesized 1H-pyrazolo
[
3,4-b]pyridine derivatives. Mainly, 3,5-disubstituted 1H-pyrazolo[3,4-
b]pyridines, 3-aryl-5-arylamino compounds (6) and 3,5-diaryl com-
pounds (8 and 9), were prepared and especially, compound 8 and 9
showed excellent DYRK1B inhibitory enzymatic activities with IC50
values of 3–287 nM. Among them, 3-(4-hydroxyphenyl), 5-(3,4-dihy-
droxyphenyl)-1H-pyrazolo[3,4-b]pyridine (8h) exhibited the highest
enzymatic (IC50 = 3 nM) and cell proliferation inhibitory activities
In order to predict the binding modes of compound 8h for DYRK1B,
we performed molecular docking studies with DYRK1B homology
model. As shown in Fig. 5, the 1H-pyrazolo[3,4-b]pyridine scaffold of
compound 8h forms two hydrogen bonds with Glu191 backbone CO and
Leu193 backbone NH in the hinge region. Also the 1H-pyrazolo[3,4-b]
pyridine ring forms hydrophobic interactions with Ala138, Val174 and
Leu246, as well as 1,2-dihydroxyphenyl ring is oriented towards solvent
exposed area by forming hydrophobic interaction with Ile117 and
hydrogen bonding with Ile117 backbone CO. Phenol ring makes elec-
trostatic interaction with Lys140, and hydrophobic interaction with
Val258.
(
HCT116, IC50 = 1.6 µM). Also compound 8h has excellent inhibitory
activities in patient-derived colon cancer organoids model as well as in
D spheroid assay model of SW480 and SW620. The docking study
3
supported that we confirmed that compound 8h binds to DYRK1B
through various hydrogen bonding interactions and hydrophobic
interactions.
4

A. Park et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128226
2
3
Aranda S, Laguna A, de La Luna S. DYRK family of protein kinases: evolutionary
relationships, biochemical properties, and functional roles. FASEB J. 2011;25:
4
49–462.
Ferrer I, Barrachina M, Puig B, et al. Constitutive Dyrk1A is abnormally expressed in
Alzheimer disease, Down syndrome, Pick disease, and related transgenic models.
Neurobiol Dis. 2005;20:392–400.
4
5
6
Ryoo S-R, Jeong HK, Radnaabazar C, et al. DYRK1A-mediated Hyperphosphorylation
of Tau. J Biol Chem. 2007;282:34850–34857.
Wegiel J, Gong C-X, Hwang Y-W. The role of DYRK1A in neurodegenerative disease.
FEBS J. 2011;278:236–245.
Jarhad DB, Mashelkar KM, Kim H-R, Noh M, Jeong LS. Dual-Specificity Tyrosine
Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential
Therapeutics. J Med Chem. 2018;61:9791–9810.
7
Kim ND, Yoon J, Kim JH, et al. Putative therapeutic agents for the learning and
memory deficits of people with Down syndrome. Bioorg Med Chem Lett. 2006;16:
3
772–3776.
8
9
Liu F, Liang Z, Wegiel J, et al. Overexpression of Dyrk1A contributes to
neurofibrillary degeneration in Down syndrome. FASEB J. 2008;22:3224–3233.
Smith B, Medda F, Gokhale V, Dunckley T, Hulme C. Recent advances in the design,
synthesis, and biological evaluation of selective DYRK1A inhibitors: a new for a
disease modifying treatment of Alzheimer‘s disease? ACS Chem Neurosci. 2012;3:
Fig. 4. Cytotoxic effect of compound 8h in patient-derived organoid model.
Colon cancer organoids were treated with 8h for 5 days and were subjected to
cytotoxicity assay using CellTiter Glo. Representative images were taken on day
8
57–872.
1
0
1
Flight MH. Neurodegenerative disease: New kinase targets for Alzheimer‘s disease.
Nat Rev Drug Discov. 2013;12:739.
Czarna A, Wang J, Zelencova D. Novel Scaffolds for Dual Specificity Tyrosine-
Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors. J Med Chem. 2018;61:
5
at 50Х. Then, organoids were stained with Hoechst33342 (nuclei), Calcein
AM (live cell) and Ethidium Homodimer-1 (dead cell). Experiments were per-
formed triplicate and quantified using Prism5.
1
7
560–7572.
1
1
2
3
Ionescu A, Dufrasne F, Celbcke M, Jabin I, Kiss R, Lamoral-Theys D. DYRK1A kinase
inhibitors with emphasis on cancer. Mini Rev Med Chem. 2012;12:1315–1329.
Zhou Q, Phoa AF, Abbassi RH, et al. Structural Optimization and Pharmacological
Evaluation of Inhibitors Targeting Dual-Specificity Tyrosine Phosphorylation-
Regulated Kinases (DYRK) and CDC-like kinase (CLK) in Glioblastoma. J Med Chem.
2
017;60:2052–2070.
1
4
Zou T, Yao S, Chen X, et al. LncRNA OIP5-AS1 regulates radioresistance by targeting
DYRK1A through miR-369-3p in colorectal cancer cell. Eur J Cell Biol. 2018;97:
3
69–378.
1
1
5
6
Rachdi L, Kariyawasam D, Aïello V, et al. Dyrk1A induces pancreatic β cell mass
expansion and improves glucose tolerance. Cell Cycle. 2014;13(14):2221–2229.
Wang P, Alvarez-Perez J-C, Felsenfeld DP, et al. A high-throughput chemical screen
reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic
beta cell replication. Nat Med. 2015;21:383–388.
1
1
7
8
Dirice E, Walpita D, Vetere A, et al. Inhibition of DYRK1A stimulates human β-cell
proliferation. Diabetes. 2016;65(6):1660–1671.
Kumar K, Man-Un Ung P, Wang P, et al. Novel selective thiadiazine DYRK1A
inhibitor lead scaffold with human pancreatic β-cell proliferation activity. Eur J Med
Chem. 2018;157:1005–1016.
1
2
9
0
Ackeifi C, Swartz E, Kumar K, et al. Pharmacologic and genetic approaches define
human pancreatic β cell mitogenic targets of DYRK1A inhibitors. JCI Insight. 2020;5
(
1).
Huang Z, Tremblay MS, Wu T-H, et al. Discovery of 5-(3,4-difluorophenyl)-3-
pyrazol-4-yl)-7-azaindole (GNF3809) for β-cell survival in type 1 diabetes. ACS
(
Fig. 5. Docking model of compound 8h for DYRK1B. Compound 8h (yellow
colored ball and stick) to the DYRK1B (blue colored ribbon). For clarity, key
binding site residues are shown in sticks and labeled using the 3-letter amino
acid code. The hydrogen bonds are displayed as green dashed lines and hy-
drophobic interactions are shown as pink dashed lines. Also electrostatic in-
teractions are indicated by orange dashed lines.
Omega. 2019;4(2):3571–3581.
21 Liu YA, Jin Q, Zou Y, et al. Selective DYRK1A Inhibitor for the Treatment of Type 1
Diabetes: Discovery of 6-Azaindole Derivative GNF2133. J Med Chem. 2020;63:
2
958–2973.
2
2
Kettle JG, Ballard P, Bardelle C, et al. Discovery and optimization of a novel series of
Dyrk1B kinase inhibitors to explore a MEK resistance hypothesis. J Med Chem. 2015;
58:2834–2844.
2
2
2
3
4
5
Chen Y, Wang S, He A, et al. Dyrk1B overexpression is associated with breast cancer
growth and a poor prognosis. Hum Pathol. 2017;66:48–58.
Declaration of Competing Interest
Friedman E. The Kinase Mirk/dyrk1B: A possible Therapeutic Target in Pancreatic
Cancer. Cancer. 2010;2(3):1492–1512.
Ashford AL, Oxley D, Kettle J, et al. A novel DYRK1B inhibitor AZ191 demonstrates
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
2
86
that DYRK1B acts independently of GSK3β to phosphorylate cyclin D1 at Thr , not
288
Thr . Biochem J. 2014;457:43–56.
26 Friedman E. Mirk/dyrk1B Kinase in Ovarian Cancer. Int J Mol Sci. 2013;14:
5
560–5575.
2
2
7
8
Anderson K, Chen Y, Chen Z, et al. Pyrido[2,3-d]pyrimidines: discovery and
preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors. Bioorg Med
Chem Lett. 2013;23:6610–6615.
Acknowledgment
Rosenthal AS, Tanega C, Shen M, et al. Potent and selective small molecule inhibitors
of specific isoforms of Cdc2-like kinases (Clk) and dual specificity tyrosine
phosphorylation-regulated kinase (Dyrk). Bioorg Med ChemLett. 2011;21:3152–3158.
This work was supported by the Korea Research Institute of Chemical
Technology [SI-1805-01 (H.L.), KK1803-F00 (K.Y.K) and SI2131-50 (K.
Y.K)].
29 Deshmukh V, O‘Green AL, Bossard C, et al. Modulation of the Wnt pathway through
inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-
modifying approach for knee osteoarthritis treatment. Osteoarthr Cartil. 2019;27:
Appendix A. Supplementary data
1
347–1360.
3
3
0
1
Shen W, Taylor B, Jin Q, et al. Inhibition of DYRK1A and GSK3B induces human
β-cell proliferation. Nat Commun. 2015;6:8381.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.128226.
G o¨ ckler N, Jofre G, Papadopoulos C, Soppa U, Tejedor FJ, Becker W. Harmine
specifically inhibitors protein kinase DYRK1A and interferes with neurite formation.
FEBS J. 2009;276:6324–6337.
3
2
Kumar K, Wang P, Sanchez R, Swartz EA, Stewart AF, DeVita RJ. Development of
kinase-selective, harmine-based DYRK1A inhibitors that induce pancreatic human
β-cell proliferation. J Med Chem. 2018;61:7687–7699.
References
1
Yoshida K. Role for DYRK family kinases on regulation of apoptosis. Biochem
Pharmacol. 2008;76:1389–1394.
5

A. Park et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128226
3
3
3
4
Ogawa Y, Nonaka Y, Goto t. Development of a novel selective Inhibitior of the Down
syndrome-related kinase DyrkA. Nat Commun. 2010;1:86.
Tahtouh T, Elkins JM, Filippakopoulos P, et al. Selectivity, Cocrystal Structures, and
Neuroprotective Properties of Leucettines, a Family of Protein Kinase Inhibitors
Derived from the Marine Sponge Alkaloid Leucettamine B. J Med Chem. 2012;55:
35 Gourdain S, Dairou J, Denhez C, et al. Development of DANDYs, New 3,5-Diaryl-7-
azaindoles Demonstrating Potent DYRK1A Kinase Inhibitory Activity. J Med Chem.
2013;56:9569–9585.
36 Neumann F, Gourdain S, Albac C. DYRK1A inhibition and cognitive rescue in a Down
syndrome mouse model are induced by new fluoro-DANDY derivatives. Sci Rep.
2018;8:2859.
9
312–9330.
6