Novel Pyrimidines as Multitarget Protein Tyrosine Kinase Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

Article abstract of DOI:10.1002/cmdc.201900606

A new class of pyrimidine derivatives were identified as potent protein tyrosine kinase (PTK) inhibitors for the treatment of idiopathic pulmonary fibrosis (IPF). Most of these small-molecule inhibitors displayed strong enzymatic activity against BTK and JAK3 kinases at concentrations lower than 10 nM. The representative compound N-(3-((5-chloro-2-(4-((1-morpholino)acetylamino)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (6 a) also exhibited high inhibitory potency toward both BTK and JAK kinase families, as well as ErbB4, at a concentration of 10 nM, achieving rates of inhibition higher than 57 %. Additionally, in vivo biological evaluations showed that 6 a can remarkably decrease the severity of IPF disease. All these investigations suggested that the multi-PTK inhibitor 6 a may serve as a promising agent for the treatment of IPF.

Full text of DOI:10.1002/cmdc.201900606

Accepted Article
Title: Novel Pyrimidines as Multi-target PTK Inhibitors for the
Treatment of Idiopathic Pulmonary Fibrosis(IPF)
Authors: Bo Sun, Xiaowen Liu, Xu Zheng, Changyuan Wang, Qiang
Meng, Huijun Sun, Xiaohong Shu, Kexin Liu, Xiuli Sun,
Yanxia Li, and Xiaodong Ma
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: ChemMedChem 10.1002/cmdc.201900606
Link to VoR: http://dx.doi.org/10.1002/cmdc.201900606
A Journal of
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ChemMedChem
10.1002/cmdc.201900606
COMMUNICATION
Novel Pyrimidines as Multi-target PTK Inhibitors for the
Treatment of Idiopathic Pulmonary Fibrosis(IPF)
[
a],1
[b],1
[b]
[b]
[b]
[b]
Bo Sun, , Xiaowen Liu, , Xu Zheng, Changyuan Wang, Qiang Meng, Huijun Sun,
[b]
[b]
[a]
[a]
[b]
Xiaohong Shu, Kexin Liu, Xiuli Sun, Yanxia Li* and Xiaodong Ma*
a
Institute of Respiratory Diseases, Department of Hematology, The First Affiliated Hospital of Dalian Medical University,
Dalian, PR China.
b
College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian, PR China.
[
a]
Dr. B Sun, Prof. X Sun , Prof. Y. Li
Department Institute of Respiratory Diseases, Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian, PR China.
No.222 Zhongshan Road, Dalian, 116022, PR China.
E-mail:liyanxia001@163.com
[b]
Dr. X Liu, X Zheng, C Wang, H Sun, Prof. L Li, K Liu, X Ma
College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian, PR China.
No.9, West section of Lvshun South Road, Dalian, Liaoning Provience, 116044, PR China.
E-mail:Xiaodong.Ma@139.com
1
B. Sun and X. Liu contributed equally to this work.
Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under :https://doi.org/xxxxxx
Abstract: A new class of pyrimidine derivatives were identified as
agents could reduce the progression of IPF, their
therapeutic effect in IPF is only moderate and do not halt or
potent Protein tyrosine kinase (PTK) inhibitors for the treatment of
Idiopathic pulmonary fibrosis (IPF). Most of these small-molecule
inhibitors displayed strong enzymatic activity against BTK and JAK3
kinases at concentrations lower than 10 nM. The representative 6a
also exhibited high inhibitory potency of BTK kinase family, JAK
kinase family, as well as ErbB4, at a concentration of 10 nM,
achieving the inhibition rates higher than 57%. Additionally, the in
vivo biological evaluation showed that 6a could remarkably reduce
the severity of the IPF disease. All these investigations suggested
that the multi-PTK inhibitor 6a may serve as a promising agent for
the treatment of IPF.
[
13]
reverse the deterioration resulting from IPF.
Accordingly, the
identification of more effective agents or drugs with new action
mechanism against IPF is still an urgent task.
Protein tyrosine kinases have been shown to participate in a
variety of signaling pathways involved in cellular homeostasis
processes that are critical to the pathogenesis of pulmonary
[14]
fibrosis.
It has also been found that PTKs regulate lung
myofibroblast proliferation via various growth factors, including
[15,16]
TGFs, EGF, PDGFRs, FGFRs, and VEGFRs.
For example,
the novel EGFR inhibitor gefitinib (5, Figure. 1), which has been
approved by the US FDA in 2003 for the treatment of non-small
cell lung cancer (NSCLC), also could produce a significant
[
15]
protective effect on lung fibrosis induced by BLM via EGF.
Idiopathic pulmonary fibrosis (IPF), characterized by scarring of
the lung tissue, could lead to serious shortness of breath, dry
[
1,2]
O
cough, inspiratory bibasilar crackles, and fatigue.
As a
N
N
N
progressive, severely debilitating disease, the median survival
time of this fatal lung disease is only between 3 and 5 years
from diagnosis. Unfortunately, the etiology and pathology of IPF
F
CN
S
[
3-6]
O
have not been elucidated to date.
Generally, IPF is thought to
NH
HN
N
O
result from epithelial cell injury and the subsequent
N
N
®
N
unconstrained fibrotic process. Pirfenidone (1, Esbriet ) and
N
N
N
®
nintedanib (2, Ofev ) are the only two drugs that have been
O
O
N
OH
approved by the U.S. Food and Drug Administration (FDA) for
the treatment of IPF. Pirfenidone works by reducing lung fibrosis
O
2
Nintedanib
Multi-PTK inhibitor
3 GLPG1690
1
pirfenidone
TGF-β inhibitor
ATX inhibitor
through downregulation of
factors and procollagens I and II,
the production of growth
(PDGF,FGF,VEGF)
[
7,8]
Cl
NH
while nintedanib, is a well-
N
N
known multi-protein tyrosine kinase (PTK) inhibitor, which can
inhibit the enzymatic activity of VEGFR1, VEGFR2, VEGFR3,
N
NH
O
HN
N
N
N
F
[
9-11]
FGFR1, FGFR2, FGFR3, PDGFα, and PDGFβ.
GLPG1690
HN
[12]
HN
N
Cl
NH
(
3),
a recently discovered autotaxin inhibitor, showed great
O
NH
O
O
O
N
O
efficacy in a bleomycin(BLM)-induced pulmonary fibrosis model
in mice and in reducing extracellular matrix deposition in the
lung. GLPG1690 is now currently being evaluated in an
exploratory phase Ⅲ study in idiopathic pulmonary fibrosis
patients (ClinicalTrials.gov Identifier: NCT03733444) (Figure 1).
Imatinib (4) is another novel multi-target inhibitor of v-Abl, c-
Kit and PDGFR, with IC50 of 0.6 μM, 0.1 μM and 0.1 μM in cell-
free or cell-based assays, respectively. Study also revealed that
imatinib displayed potential efficacy to treat fibrotic lung disease
N
N
N
O
4
Imatinib
6a Pyrimidine
Multi-PTK inhibitor
IC50(JAK3, BTK, EGFR)<10 nM
5
Gefitinib
EGFR inhibitor
Multi-PTK inhibitor
( v-Abl, c-Kit and PDGFR)
Figure 1. Chemical structures of the novel anti-IPF agents
Janus kinase 3 (JAK3), which belongs to the janus family of
kinases, is involved in signal transduction by receptors that
employ the common gamma chain (γc) of the type I cytokine
(
ClinicalTrials.gov Identifier: NCT00131274). Although these
1
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10.1002/cmdc.201900606
COMMUNICATION
receptor family (e.g. IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, and IL-
conditions at reflux temperature, the desired molecules 6a-i
were produced with yields in the range of 16-40%.
2
1R). Signaling through the IL-15 receptor is known to be
[17,18]
important in the development.
Recent studies showed that
Kinase can react with ATP-binding substrate, and then activates
disease-related signaling pathways. While ATP is converted to
ADP. According to this mechanism, the ADP-Glo™ Kinase
Assay (Promega, US), which is a luminescent ADP detection
assay, provides a universal, homogeneous, high-throughput
screening method to measure kinase activity by quantifying the
JAK-STAT signaling play an important role in the pathogenesis
of pulmonary fibrosis, and thus inhibition JAK-STAT signaling in
[
19-22]
fibroblasts may be effective in the treatment of fibrosis.
Bruton's tyrosine kinase (BTK) is type of kinase protein
expressed in B lymphocytes and T cells.
a
[23]
BTK deficiency in
[
31-34]
humans is associated with reduction in TNF-α production by
activated monocytes. Thus, inhibition of BTK activity can provide
a useful treatment for allergic disorders, autoimmune, and/or
inflammatory diseases such as, rheumatoid arthritis, idiopathic
thrombocytopenic purpura, asthma, and other related disorders.
amount of ADP produced during a kinase reaction.
All the
title molecules were biologically evaluated for their activity
against BTK and JAK3 enzymes using this method. The assay
results are presented in Table 1. Clearly, most of these
compounds exhibited strong inhibitory activity against both BTK
and JAK3 enzymes at concentrations around 10 nM. In terms of
their activity against BTK kinase, more than half of the title
molecules (6a,c,d,g, and i) had IC50 values lower than 1 nM. The
representative molecule, 6a, displayed the strongest enzymatic
activity against BTK kinase, with an IC50 value of 0.6 nM. As for
their activity against JAK3 enzyme, compounds 6a, 6c, and 6d
exhibited very high inhibitory activity, with IC50 values of 0.59,
1.08, and 1.22 nM, respectively. Notably, compound 6a, the
strongest BTK inhibitor, also has the most potent inhibitory
activity against JAK3 kinase, with an IC50 value of 0.59 nM.
Moreover, compound 6a has low toxicity against the normal
human bronchial epithelioid (HBE) cells at concentration lower
than 2.78 µM. In addition, compound 6a displayed a moderate
ClogP value (4.46), showing its good overall capability to
[
24,25]
Due to our great interest in the identification of potent BTK
[
26-28]
inhibitors for the treatment of B-cell lymphoma,
we
accidentally obtained a class of pyrimidine derivatives, which
exhibited strong activity against BTK, JAK3, and EGFR kinases
at a drug concentration of 10 nM or less. Considering the
important role of these kinase in the development of IPF, we
believe that these multi-PTK inhibitors are effective in treatment
of the IPF disease. Therefore, herein, we describe in detail these
pyrimidine derivatives, along with their synthesis, and the data of
their biological activity against IPF in vivo and in vitro.
R1
N
NH2
R1
Cl
NO2
N
R1
N
NH
a,b
N
Cl
N
Cl
c
[
35,36]
NH
HN
HN
N
NH
penetrate the cell membrane.
NH2
O
1
N
O
9
9
a R = Cl
H
All these test results clearly indicated that these structural
modifications, which were inspired by our previous structure and
activity relationship (SAR) explorations are rational and effective.
Moreover, this study further confirmed the benefit of 1-
substitutedacetamide linker in the C-2 aniline, and revealed that
the morpholine substituent (6a,c,d,h) in the C-2 aniline side
chain of the pyrimidine core is more favorable than the
piperazine ring (6b,e,f,g) at the same position. Apparently, 6c
(0.6, 1.08 nM ) increased 2-12 times higher capability than 6e
(12.5, 14.0 nM) and 6f (14.9, 1.82 nM) for inhibiting both BTK
and JAK3 enzymatic activity. In terms of R2 group, the
methyl(6d) and methoxy substituents(6c) exhibited equivalent
anti-enzymatic activity to 6a(H). While the nitro group (6h) in R1
produced strong inhibitory effect on BTK kinase(0.6 nM), but
14.5 times lost activity against JAK3(8.53 nM) compared with 6a
(0.59 nM). Although the dibutylamine substituent (6h) is effective
for inhibiting BTK (0.6 nM) and JAK3 (4.9 nM) enzymatic activity,
its ClogP value is very high (6.78), indicating its weak ability to
penetrate lung tissue.
7
8
1
g
b R = NO
R2
O
2
NH
NO2
NO2
NH2
O
NO2
NH2
N
d
R2
O
e
R2
O
f
R2
O
X
R2
HN
HN
HN
6a-i
R = Cl, NO2;
R = MeO,Cl,H
X= O, MeN, EtN
1
Br
N
N
2
X
X
1
0a-c
11a-c
12a-d
X= O, MeN, EtN
R = MeO,Cl,H
1
3a-d
X= O, MeN, EtN
R = MeO,Cl,H
2
R = MeO,Cl,H
2
2
Scheme 1. Synthetic route of title compounds 6a-i. Reagents and conditions:
a) acryloyl chloride, NaHCO , CH CN, 0 C, 0.5 h, 95%; (b) Fe-NH Cl, MeOH-
O, 2 h, 70 C, 81%; (c) ArNH , DIPEA, 1,4-dioxane, 60 C, 2 h, 82-91%; (d)
bromoacetyl bromide, NaHCO , CH CN, 0 C, 0.5 h, 97%; (e) morpholine,
CO , KI, CH CN, reflux, 5 h, 81%; (f) Fe-NH Cl, MeOH-H O, 2 h, 70 C,
2%; (g) TFA, 2-BuOH, 100C, 12 h, 16-40%.
(
3
3
4
H
2
2
3
3
K
2
3
3
4
2
8
The synthetic route of the title compounds 6a-i is depicted in
[
29,30]
Scheme 1.
Based on our previously reported method, the 2-
[
a]
chloropyrimidine derivatives 9a,b, which were the key
intermediates to prepare the pyrimidine template, were
conveniently synthesized by acylation, reduction, and
nucleophilic substitution reactions, with 70% overall yields for
the three steps. Additionally, the key intermediates, C-2 aniline
side chains 13-d, were generally synthesized via acylation,
substitution and reduction reactions starting from the commercial
material 4-nitroanilines 10a-c. Ultimately, by coupling anilines
Table 1. In vitro enzymatic activity of the title compounds 6a-i.
R1
N
HN 2 N NH
4
1`
2
`
`
R2
3
NH
R
O
13a-d with the pyrimidines 9a,b under trifluoroacetic acid(TFA)
Enzymatic activity
[
b]
[d]
(
IC50, nM)
Toxicity to HBE
cells
CLogP
2
1
[c]
Compd.
R
R
H
R
(
IC50, μM )
BTK
JAK3
NH
6a
6b
6c
O
O
O
Cl
Cl
Cl
0.60±0.08
1.00±0.11
0.60±0.09
0.59±0.09
6.25±1.02
1.08±0.19
2.78±0.87
0.32±0.02
3.20±0.56
4.46
3.97
3.85
N
O
NH
Me(3`)
N
N
NH
MeO(3`)
N
O
2
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10.1002/cmdc.201900606
COMMUNICATION
NH
6
6
6
6
6
6
d
e
f
O
Me(3`)
MeO(3`)
MeO(3`)
Me(3`)
H
Cl
0.50±0.09
12.5±1.2
14.9±2.1
11.2±1.4
0.60±0.07
0.60±0.09
1.22±0.31
14.0±2.14
1.82±0.77
3.12±0.84
8.53±0.95
4.90±0.99
1.20±0.12
4.31
2.91
3.50
3.43
3.70
6.78
N
O
NH
O
O
O
O
Cl
1.14±0.09
0.45±0.07
0.55±0.06
7.29±0.21
35.9±3.15
>10
N
N
N
N
O
NH
Cl
N
NH
g
h
i
Cl
N
NH
NO
2
2
N
NH
O
H
NO
N
nintedanib
[a] The data were means ±SD of three separate experiments. [b] The enzymatic activity against BTK and JAK3 enzymes using the ADP-GloTM kinase assay. [c]
The toxicity effects on the proliferation of normal HBE cells were determined by the CCK-8 assay. [d] CLogP means Calculated LogP which is oil-water partition
coefficient.
To confirm the selectivity of these novel BTK and JAK3 dual
inhibitors, the biological activity of the potent inhibitor 6a against
Control BLM 6a Nida
a panel of 411 kinase was also analyzed (SI-2) using the
p-Erk1/2
Erk1/2
44/42kDa
SelectScreen™ Biochemical Profiling Lab platform (Thermo-
[37,38]
Fisher Scientific, Waltham, MA, USA).
The results of this
44/42kDa
88kDa
analysis (Table 2) revealed that, in addition to JAK3 and BTK
kinases, compound 6a strongly binds to other kinases, including
members of the BTK family (BLK, BMX and TEC) and JAK
family (JAK1, JAK2), as well as ErbB4, FLT3 D835Y and TXK,
at a concentration of 10 nM, reaching inhibition rates higher than
p-STAT3
STAT3
88kDa
p-Smad2/3
5
2/60kDa
57%. Remarkably, compound 6a also exhibited strong inhibitory
potency of FLT3 (54%), FLT3 D385Y (82%), RET (59%), RET
V804L (55%) and RET Y791F (50%), suggesting that this
compound may be useful for the treatment of several types of
cancer. From this investigation, it can be confirmed that most of
these pyrimidines are pan-active kinase inhibitors, which may
act with the kinase by forming the strong covalent bond between
Smad2/3
52/60kDa
42kDa
β-Actin
Figure 2. Compound 6a inhibits the activation of STAT and related signaling in
C57BL/6 mouse lung tissue. After administration of drug for 15 days, the lung
tissue of C57BL/6 mice was grinded, homogenized and lysed to extract
proteins. The protein was then performed the Western blot test according to
the general test method. β-Actin is used as control, the values are relative to
β-Actin. Data are presented as the mean ±SD (n = 8). p < 0.05.
[39,40]
the acryloyl moiety and cysteine reside in these proteins.
While for nintedanib, its targeted kinases include all three
VEGFR subtypes (IC50, 13–34 nM), PDGFRa and PDGFRh (IC50
,
5
9 and 65 nM), and FGFR types 1, 2, and 3 (IC50, 69, 37, and
B
108 nM, respectively).
A
a
Table 2. Selectivity profile of compound 6a against a panel of 411 kinases
b
Kinase
%
Kinase
%
Kinase
%
BRAF V599E
BTK
21
97
30
30
51
62
40
78
35
15
23
17
22
19
11
50
86
AURKA (Aurora A)
AURKB (Aurora B)
AURKC (Aurora C)
BLK
52
50
33
66
92
23
17
30
47
55
89
79
2
IRAK4
15
28
57
57
45
33
95
17
9
ITK
RET G691S
RET M918T
RET V804M
STK16 (PKL12)
STK33
JAK1
JAK2
BMX
JAK2
EGFR
JAK2 V617F
JAK3
EGFRL858R
EGFRL861Q
EGFRT790M
EGFRT790M L858R
EGFR d746-750
ERBB4
C
D
TEC
NEK7
WEE1
NEK9
ABL1
NTRK1 (TRKA)
NTRK2 (TRKB)
NTRK3 (TRKC)
RET
39
39
31
59
55
50
27
21
ABL1 E255K
ABL1 G250E
ABL1 T315I
ABL1 Y253F
ABL2(Arg)
NUAK1 (ARK5)
TXK
FLT1 (VEGFR1)
FLT3
54
82
38
58
RET V804L
RET Y791F
ROS1
FLT3 D835Y
FLT4 (VEGFR3)
FLT3 ITD
SYK
Figure 3. In vivo effect of 6a on BLM-induced BLM-induced pulmonary
fibrosis . Mice were intratracheally instilled with BLM (1.5 mg/kg) or with
vehicle only. The indicated dose (30 mg/kg) of 6a and nintedanib were given
once daily for 14 days after BLM challenge (n = 8 per group). Section of lung
tissue was prepared on day 14 after BLM treatment and subjected to
a
This test was conducted by the SelectScreen™ Biochemical Profiling Lab.
Two separate experiments were performed, and the averaged data was
dicipated. Inhibition rate at a concentration of 10 nM, Only the inhibition rate
more than 10% was showed in this table.
b
3
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Trichrome Masson staining (200×). (A: The control group, B: The BLM model
group, C: The BLM model plus nintedanib group, D: The BLM model plus 6a
group).
examined using a murine experimental model of BLM-induced
[41]
lung neutrophilic inflammation.
Nintedanib was used as a
positive control. The deposition of collagen fibers was assessed
by Masson’s trichrome staining. The results showed in Figure 3
clearly indicated that compound 6a remarkably reduced the
severity of the inflammation compared with the control group. In
addition, as showed in Figure 4, three typical biomarkers of the
degree of pulmonary fibrosis (TGF-β1, IL-1β, and
hydroxyproline) were also detected in the lung tissues of the
experimental mice. Evidently, all the three biomarkers in the 6a-
treated groups were apparently reduced compared with those in
the nintedanib-treated groups, showing its superior biological
activity against IPF.
In addition, the most active JAK3 and BTK dual inhibitor 6a
was also explored its inhibitory effects on active signaling by
using western blot analysis. The novel agent nintedanib was
[41-43]
also tested for comparsion.
As showed in Figure 2, after
treating the C57BL/6 mice with both 6a and nintedanib at a dose
of 30 mg/kg daily (qd) over a 14-day period, the phosphorylation
of Erk1/2, STAT3, Smad2/3 were clearly inhibited by 6a. The
particular result that the phosphorylation of Erk1/2 was almost
completely repressed by compound 6a indicates its
improved inhibitory effects on Erk1/2 protein compared with that
of nintedanib. However, the BTK protein was not detected in the
lung tissue of this mouse model (which was not shown in this
Figure 2), showing that BTK was not a key therapeutic target for
IPF disease. Therefore, the multi-kinase inhibitor 6a may play its
therapeutic effects through other signaling pathway despite its
strong activity against BTK kinase.
To investigate the interaction mechanism of the title molecules
with BTK and JAK3 enzymes, the representative compound 6a
was docked into the ATP binding pocket of each, the BTK (PDB
[44]
[45]
ID: 3GEN)
and JAK3 (PDB ID: 4Z16)
proteins. The
AutoDock 4.2 software and its default parameters were used to
[46,47]
conduct the structural analysis.
The results shown in Figure
5
indicated that the structures displayed a very special and
strong covalent- and hydrogen-bond network in the ATP binding
pocket. Importantly, the essential acrylamide functional group of
compound 6a forms a strong covalent bond with the amino acid
Cys481 in the BTK enzyme, and the amino acid Cys909 in the
JAK3 protein. In addition, the hydrogen-bond interactions formed
by the N-2 atom of the pyrimidine core with the amino acid
Leu488 in BTK, and with the amino acid Leu905 in JAK3 were
also present. For compound 6a, the carbonyl group in the C-2
aniline side chain also forms additional hydrogen bonds with the
amino acids Leu528 in BTK and Gly908 in JAK3. Additionally,
the morpholine substituent reaches into the hydrophilic section
surrounded by the amino acids Val537 and Sep538 in BTK, and
Val912 and Val838 in JAK3. The chlorine atom at the C-5
position of the pyrimidine core serves as a base to interact with
the amino acid side chain of Lys430 in BTK and Leu956 in JAK3.
All these important interaction forces produced the strong anti-
BTK and -JAK enzymatic activity.
Figure 4. Compound 6a treatment reduced BLM-induced lung inflammati去啊
Ytfgand fibrosis in vivo evaluation, the mediator concentrations in whole-lung
homogenates were determined by ELISA: a)TGF-β1, b)hydroxyproline, and
c)IL-1β in lungs homogenate were determined as described in the methods.
Data are presented as the mean ±SD (n = 3).
The effects of compound 6a on Leukotriene B4(LTB4)
production and neutrophil infiltration in vivo were further
B
A
[
44]
[45]
Figure 5. Putative co-structure of compound 6a bound to the ATP binding site of BTK (PDB ID: 3GEN)
and JAK3 (PDB ID: 4Z16)
.
To effectively treat the most lethal diffuse fibrosing lung disease
IPF, a new series of pyrimidine derivatives were synthesized
kinases including members of the BTK family (BLK, BMX and
TEC), JAK family (JAK1, JAK2), as well as ErbB4, FLT3 D835Y
and biologically evaluated in vivo and in vitro activity in this study. and TXK at a concentration of 10 nM, with inhibition rates higher
Most of these small molecules displayed strong dual inhibitory
effect on the BTK and JAK3 enzymatic activities at
concentration of 10 nM or less. Additionally, the most active
than 57%. Furthermore, compound 6a remarkably reduced the
three typical biomarkers of the degree of pulmonary fibrosis
(TGF-β1, IL-1β, and hydroxyproline) in the lung tissues of the
experimental mice, showing its slightly higher efficacy than that
a
inhibitor 6a also exhibited strong inhibitory activity against other
4
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ChemMedChem
10.1002/cmdc.201900606
COMMUNICATION
of nintedanib in the in vivo biological evaluation. Overall, this
contribution provides a novel multi-PTK inhibitor, 6a, as a
promising agent for the treatment of the IPF disease.
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We are grateful to the “Xing Liao” Talents Project of Liaoning
province, China (XLYC1807011), the Research Fund of Higher
Education of Liaoning province (LQ2017008, LQ2017039), the
Natural Science Foundation of Liaoning province (20180530066),
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Keywords: IPF • PTK • multi-target • inhibitors • pyrimidine
ABBREVIATIONS
IPF, Idiopathic pulmonary fibrosis; NSCLC, Non-small cell lung
cancer; PTK, Protein tyrosine kinase, BLM, bleomycin; JAK3,
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Janus kinase 3; BTK,
Bruton's tyrosine kinase; TFA ,
trifluoroacetic acid; DAPIA, N,N-Diisopropylethylamine; BLK, B-
Lymphoid tyrosine kinase; BMX, Bone marrow tyrosine kinase
on chromosome X; TEC, tyrosine kinase expressed in
hepatocellular carcinoma; FLT3,Fms-like tyrosine kinase 3; RET,
rearranged during transfection; CLogP, Calculated LogP(oil-
water partition coefficient); Erk1/2, extracellular regulated
kinases 1/2; STAT3, Signal transducers and activators of
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Entry for the Table of Contents
Pyrimidine scaffold
Protein
Cys
Cl
N
S
HN
N
NH
Covalent bond
O
N
N
O
H
NH
6a
O
Multi-PTK inhibitor for treatment of IPF
IC50(JAK3)=0.59 nM, IC50(BTK)=0.6 nM



Novel pyrimidines as potent PTK inhibitors for treatment of IPF.
They displayed strong enzymatic activity against BTK and JAK3 kinases(IC50<10 nM).
6a remarkably reduced the severity of the IPF disease in vivo biological evaluation.
7
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