Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis

Article abstract of DOI:10.1021/acsmedchemlett.7b00164

Idiopathic pulmonary fibrosis (IPF) is a serious and deadly disease for which treatment options are limited. The recent approval of antifibrosis agent nintedanib represents one of the first therapeutic approaches for the treatment of IPF. Here, we report novel indolinone-based multikinase inhibitors that target angiogenesis and fibrosis pathways and may serve as potential therapeutics for IPF. KBP-7018 is a novel, tyrosine kinase-selective inhibitor with potent effects on three fibrotic kinases (c-KIT, PDGFR, and RET). The pharmacokinetics (PK) properties of KBP-7018 were favorable in mice, rats, and dogs. In a bleomycin (BLM)-induced mouse pulmonary fibrosis model, 10, 30, and 100 mg/kg daily doses (q.d.) of KBP-7018 improved the 28-day survival rate in a dose-dependent manner. The improved efficacy of KBP-7018 compared to nintedanib provided a certain level of chemical validation for the involvement of PDGFR, c-KIT, and RET in IPF. Thus, KBP-7018 represents a novel multikinase inhibitor with differentiated activity, highly enhanced selectivity, and acceptable PK profiles that will enter phase I clinical trials.

Full text of DOI:10.1021/acsmedchemlett.7b00164

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Letter
Discovery of Indolinone-based Multi-kinase Inhibitors as
Potential Therapeutics for Idiopathic Pulmonary Fibrosis
Zhenhua Huang, Heran Li, Qian Zhang, Fangzheng Lu, Mei Hong,
Zhigang Zhang, Xiaocui Guo, Yuanju Zhu, Sanming Li, and Hongzhuo Liu
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00164 • Publication Date (Web): 30 Sep 2017
Downloaded from http://pubs.acs.org on October 1, 2017
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ACS Medicinal Chemistry Letters
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Discovery of Indolinone-based Multi-kinase Inhibitors as Potential
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Zhenhua Huang† Heran Li†, Qian Zhang‡, Fangzheng Lu†, Mei Hong‡, Zhigang Zhang‡, Xiaocui Guo‡,
Yuanju Zhu‡, Sanming Li† and Hongzhuo Liu†*
†School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, P. R. China;
‡KBP Biosciences, 401, Building 2, Jinan Pharm Valley, North Section of Gangxing Three Road, Jinan, Shandong, 250101,
P. R. China
KEYWORDS: idiopathic pulmonary fibrosis (IPF); multi-kinase inhibitors; SAR; PK properties; in vivo study.
100
Sham
90
Model
Nintedanib 100mg/kg, q.d
O
O
80
70
60
50
40
Nintedanib 30mg/kg, q.d
N
N
**
KBP-7018 100mg/kg, q.d
KBP-7018 30mg/kg, q.d
KBP-7018 10mg/kg, q.d
*
**
*
Log-rank test
*P<0.05
**P<0.01
NH
IC50: c-KIT 10 nM
RET 7.6 nM
PDGFR: 25 nM
O
O
N
0
5
10
15
20
25
30
28
H
Administration day
3
O
ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a serious and deadly disease for which treatment options are limited. The reꢀ
cent approval of antiꢀfibrosis agent nintedanib represents one of the first therapeutic approaches for the treatment of IPF. Here, we
report novel indolinoneꢀbased multiꢀkinase inhibitors that target angiogenesis and fibrosis pathways and may serve as potential
therapeutics for IPF. KBPꢀ7018 is a novel, tyrosine kinaseꢀselective inhibitor with potent effects on three fibrotic kinases (cꢀKIT,
PDGFR, and RET). The pharmacokinetics (PK) properties of KBPꢀ7018 were favorable in mice, rats and dogs. In a bleomycin
(BLM)ꢀinduced mouse pulmonary fibrosis model, 10, 30, 100 mg/kg daily doses (q.d.) of KBPꢀ7018 improved the 28ꢀday survival
rate in a doseꢀdependent manner. The improved efficacy of KBPꢀ7018 compared to nintedanib provided a certain level of chemical
validation for the involvement of PDGFR, cꢀKIT and RET in IPF. Thus, KBPꢀ7018 represents a novel multiꢀkinase inhibitor with
differentiated activity, highly enhanced selectivity and acceptable PK profiles that will enter phase I clinical trials.
required cellular homeostasis, including the pathogenesis of pulꢀ
monary fibrosis3. Based on accumulating evidences from both in
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease
that has a median survival time of 2ꢀ3 years. Its therapeutic opꢀ
tions were limited until the approval of pirfenidone and nintedanib
(compound 1 and 2, Figure 1) in 20141. Although both drugs reꢀ
vitro studies and in vivo animal models, tyrosine kinases mediated
ceived the breakthrough drug designation from the FDA to faciliꢀ
tate rapid approval, their efficacy in IPF is only moderate.
Pirfenidone and nintedanib significantly slow the rate of disease
progression. However, they do not halt or reverse the deterioration
of IPF and therefore have shown no benefit in the overall survival
of patients. Accordingly, a significant unmet medical need is in
the management and reversal of IPF2.
lung myofibroblast proliferation via plateletꢀderived growth factor
(PDGFRs), fibroblast growth factor receptors (FGFRs) and vascuꢀ
lar endothelial growth factor receptors (VEGFRs). Nintedanib, a
wellꢀknown multiꢀtyrosine kinase inhibitor that blocks VEGFR1,
VEGFR2, VEGFR3, FGFR1, FGFR2, FGFR3, PDGFα and
PDGFβ, was originally used as a treatment of nonꢀsmall cell lung
cancer4ꢀ6. Remarkably, nintedanib was later recognized as a potent
inhibitor of lung fibrosis in an animal model, which encouraged
its study in clinical trials and the subsequent approval as a treatꢀ
ment for IPF7, 8. However, potential side effects, including the
inhibition of the human etherꢀaꢀgoꢀgo related gene potassium
channel (hERG K, IC50 2.6 µM), and the rather low oral bioavailꢀ
ability of nintedanib (4.7%) limited its application. More imꢀ
Although the etiology and pathology of IPF have not yet been
elucidated, IPF is considered to result from epithelial cell injury
and the subsequent unconstrained fibrotic process. Tyrosine kiꢀ
nases are believed to be involved in a range of signaling pathways
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portantly, nintedanib has a very narrow therapeutic window,
A different synthetic route was developed to prepare the pyrroliꢀ
1
2
3
4
5
6
7
8
which prompted us to structurally modify this compound. Based
on the SAR studies of nintedanib, 6ꢀmethoxycarbonylꢀsubstituted
indolinones were key structures that possessed a potent inhibitory
effect on VEGFR, PDGFR and FGFR. Therefore, the related inꢀ
dolinone in the parent compound was chosen as a starting point to
optimize the inhibitory effect on kinases. We adopted a shapeꢀ
based scaffold hopping approach to convert region 1 of nintedanib
to a dihydroindole ring to yield series 9 and oxypyrrolidine to
yield series 15 and 17, thus enabling rapid optimization. In addiꢀ
tion, we introduced alternative isosteres in region 2 of nintedanib.
Finally, several additional isosteres were prepared with a modifiꢀ
cation at the Cꢀ6 position of indole ring in the parent compound to
produce series 21 with diverse chemotypeꢀbased selections. A
detailed description of these compounds has been recently reportꢀ
ed9. Here, we report the design, synthesis, SAR, PK properties,
and in vivo efficacy of indolinoneꢀbased kinase inhibitors using
nintedanib as the lead compound. The optimization of the lead
compound 2 to compound 3 (belonging to series 9, also named
KBPꢀ7018) produced a compound that targeted PDGFR, cꢀKIT,
and RET with high selectivity. Changes in region 1 (the aryl ring)
exerted a profound effect on the overall selective inhibitory efꢀ
fects on tyrosine kinase. A novel tyrosine kinase inhibitor 3 sigꢀ
nificantly reduced the inhibitory effects on hERG K compared
with the parent compound (nintedanib). This compound will soon
enter phase I clinical trials.
done derivatives of nintedanib by adapting known procedures,
which was described in Scheme 2. The tosylation of starting alcoꢀ
Scheme 2. Preparation of compounds 15 and 17.
Br
O
O
R2
N
R1
R2
O2N
12
N
iv
N
i, ii
N
O
O
R1
N
N
iii
H
H
OH
N
13
14
R1
10
11
R2
O2N
H2N
i-v
R1
9
N
R1
O
R2
N
N
N
8
HO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
R2
v
O
N
H
16
NH
NH
O
O
O
O
N
H
N
H
15
17
O
O
Reagents and conditions: i. tosyl chloride (TsCl), DCM, 4ꢀ
dimethylaminopyridine (DMAP), TEA, 0 ; ii. HNR1R2, MeCN,
K2CO3, reflux; iii. Cs2CO3, tris(dibenzylideneacetone)dipalladium
(Pd2(dba)3), Xantphos, dioxane, reflux; iv. MeOH, Pd/C, H2, rt; v.
MeOH, reflux.
hol 10 was followed by a displacement reaction to generate the
amine group, resulting in compound 11. Coupling compound 11
with 4ꢀnitrobromobenzene 12 under Buchwald conditions affordꢀ
ed an aryl lactam to produce compound 13. Afterwards, the nitro
group in compound 13 was hydrogenated to yield an aniline group
in compound 14. The coupling of compound 14 and enol ether 8
provided the final compounds 15. Compound 17 was synthesized
using a similar method as shown in Scheme 2, with the exception
that compound 16 were substituted for its isomer 10.
region 2
region 1
O
O
O
N
N
N
N
N
NH
O
NH
O
N
O
O
Me
N
O
H
N
1
2
3
H
O
O
Several additional analogs of nintedanib were prepared by introꢀ
ducing modifications at the Cꢀ6 position 4 (Scheme 3). The substiꢀ
tuted lactam in compound 18 was condensed with trimethylorthoꢀ
benzoate in acetic anhydride to yield enol ether 19, which was
coupled with the aniline in compound 20 under basic conditions
to provide compounds 21aꢀg. Under wellꢀestablished conditions,
the bromo intermediate 21a was converted to the boronate 22,
which was coupled to different aryl halides under Suzuki condiꢀ
Figure 1. The chemical structures of pirfenidone 1, the lead comꢀ
pound nintedanib 2, and compound 3 (KBPꢀ7018)
The synthesis of compounds 9 is shown in Scheme 1. The acylaꢀ
tion of indoline 4 yielded the chloroacetamide 5, followed by a
displacement reaction with various amines to yield compound 6.
Next, the reduction of the nitro group in compound 6 afforded an
amino group (compound 7), which was coupled to a known enol
ether 8 to produce compounds 94. Products were obtained as hyꢀ
drochlorides to improve their solubility for subsequent in vitro
and in vivo tests.
tions to produce compounds 21g and 21h 10
.
Scheme 3. Preparation of compound 21.
O
O
N
N
N
N
N
N
Scheme 1. Preparation of compound 9.
O
21a R=Br
20
H2
N
O
i
NH
O
O
21b R=OCF3
N
H
R
N
H
ii
R
21c R=5-
oxadiazolyl
18
19
N
H
R
21d R=3-
oxadiazolyl
21e R=5-(2-N-methyl)tetrazolyl
21f R=5-oxazoly
O
O
O
N
N
N
N
N
N
N
N
N
NH
iii
iv
NH
O
NH
O
O
N
Br
O
N
H
N
R
B
H
21g R=2-furanyl
21h R=2-triazolyl
21a
H
O
22
Reagents and conditions: i. chloroacetyl chloride, dichloroꢀ
methane (DCM), trimethylamine (TEA), ꢀ20 , 90%; ii. HNR1R2,
methyl cyanide (MeCN), K2CO3, reflux, 55%; iii. Methanol
(MeOH), Pd/C, H2, room temperature (rt), 92%; iv. MeOH, reflux,
67%.
Reagents and conditions: i. Trimethylorthobenzoate, acetic anhyꢀ
dride, reflux; ii. MeOH, KOH, 50°C; iii. bis(pinacolato)diboron,
potassium
acetate
(KOAc),
PdCl2(bis(diphenylphosphino)ferrocene) (PdCl2(dppf)), dioxane,
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100°C; iv. 21g: 2ꢀbromofuran, Cs2CO3, PdCl2(dppf), dioxane,
H2O, 100°C; 21h: 3ꢀchloroꢀ4ꢀ(4ꢀmethoxybenzyl)ꢀ4Hꢀ1,2,4ꢀ
triazole, Cs2CO3, PdCl2(dppf), dioxane, H2O, 100°C, 30% folꢀ
lowed by trifluoroacetic acid (TFA), 110°C, microwave.
1
2
3
Table 1. The SAR of indoline derivative 9.
O
R1
N
4
5
N
R2
6
7
8
9
NH
O
9
O
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
NR1R2/R
IC50 (nM)
IC50 (ꢁM)
hERG K
NA
FGFR1
140
PDGFRβ
15
VEGFR2
65
3T3 (hꢀPDGFbb)
NA
9a, NMe2
N
O
6600
1800
620
91
19
15
24
300
230
100
300
150
260
100
110
>30
>30
>30
>30
9b,
9c,
N
O
N
N
N
9d,
N
4700
N
O
9e,
3,
N
1600
41
25
110
3.1
100
85
>30
2.6
2, Nintedanib
1.8
NA: not available. The data were presented with two significant figures due to standard experimental error.
against hERG K compared to nintedanib. Furthermore, the subꢀ
stituents other than morpholine (eg. 9bꢀe) also reduced the hERG
K inhibitory effect.
Because of its high potency and minimal effects on hERG K,
compound 3 (KBPꢀ7018) is a promising kinase inhibitor. Based
on the additional physicochemical properties of compound 3, such
as its acceptable solubility and clean properties, we evaluated this
compound in subsequent tests.
When evaluating compounds for their kinome selectivities,
PDGFR was chosen as the key target due to its critical role in the
initiation and progression of IPF. Therefore, the initial strategy
was to improve the drugꢀlike properties and potency of nintedanib
(2) against PDGFR. Derivatives of compound 9 containing dihyꢀ
droindole groups were designed and synthesized by introducing a
variety of amines (Table 1). In all cases, the inhibitory activities
of each derivative toward FGFR and VEGFR were weaker than
nintedanib, indicating that the dihydroindole core may not be
optimal for improving the efficacy against FGFR and VEGFR.
Fortunately, the compounds showed a reserved affinity for
PDGFR, with IC50 values ranging from 10ꢀ100 nM. A compound
with a small Me2N group (compound 9a) exhibited a reasonable
inhibitory potency (IC50, 15 nM), whereas a compound with a
larger amino group (9b) exhibited a loss of activity. Surprisingly,
neither the removal of the basicity of the nitrogen (9c) nor the
aromatization of the amino group (9d and 9e) had an impact on
potency. The morpholinylꢀbearing compound 3 (KBPꢀ7018) also
inhibited PDGFR activity, despite the lack of affinity for FGFR
and a decreased inhibition of VEGFR. Taken together, basicity
was not a prerequisite for high inhibitory potency against PDGFR,
and as various basic groups with different pKa values were all
tolerated, the dihydroindol core may play a key role in affinity to
the hinge region of the PDGFR. Because an Xꢀray structure of
PDGFR is not available, a detailed explanation of its activity is
beyond the scope of the present study.
The lactam 15 and 17 showed similar SAR trends in PDGFR acꢀ
tivity. However, the affinities for FGFR1 and VEGFR were inꢀ
creased compared with compounds 9bꢀf (Table 2). Both Sꢀ
enantiomer (15a) and Rꢀenantiomer (15b) of piperizinyl comꢀ
pounds showed a comparable potency to nintedanib against both
VEGFR and PDGFR, whereas the activity in FGFR1 was deꢀ
creased. On the other hand, a Me2N analog (15c) also showed
decreased activities against PDGFR, FGFR1 and VEGFR comꢀ
pared with nintedanib. Furthermore, the isomeric piperazinyl anaꢀ
log (17a), a racemate, did not show activity against PDGFR,
whereas individual enantiomers (17b and 17c) were also active in
cells with potencies similar to compounds 9bꢀe and 3. Disappointꢀ
ingly, the presence of the piperazine nucleus elicited a significant
inhibitory effect of hERG K, such as in compound 15a (IC50, 0.95
ꢁM against hERG K). Therefore, these compounds were not suitꢀ
able for further optimization.
Because the ester group is regarded as a metabolic liability (Table
2), we next performed SAR studies by modifying the substituent
in position 6 of the indolinone group with various isosteric groups.
All isosteric heterocycles showed reasonable potencies against
FGFR, PDGFR and VEGFR compared with nintedanib. The triaꢀ
zole derivative 21h provided the desired potency, whereas 5ꢀ
oxazoleꢀbearing compound 21f was the least potent. Most of the
other compounds, such as 21c and 21h, had nanomolar potencies
against PDGFR and reasonable activities against FGFR1 and
VEGFR.
The designed compounds were further evaluated for their abilities
to inhibit the hꢀPDGFꢀbbꢀstimulated proliferation of 3T3 cells.
Compounds 9bꢀf and 3 were potent in the ~100 nM range, indicatꢀ
ing sufficient cell permeability. Compounds with high potencies
were further evaluated for their effects on the hERG K. To our
surprise, a morpholino substituent at region 2 (compound 3, also
known as KBPꢀ 7018) significantly reduced the inhibitory effects
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Table 2. The SAR of the indoline derivatives 15, 17 and 21.
Page 4 of 7
1
2
3
R1
N
O
R1
N
O
R2
N
N
N
N
O
N
R2
4
5
6
7
8
NH
NH
O
21
NH
O
O
O
O
N
N
H
H
N
R
15
17
O
O
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NR1R2/R
IC50 (nM)
IC50 (ꢁM)
hERG K
0.95
FGFR1
120
PDGFRβ
4.3
VEGFR2
1.6
3T3 (hꢀPDGFbb)
110
N
N
15a, (S),
15b, (R),
N
N
100
3.2
8.3
97
1.4
15c, NMe2
94
14
45
51
12
NA
NA
NA
NA
N
N
140
17a,
17b, (R or S)
17c, (R or S)
21b, OCF3
21c, 5ꢀoxadiazolyl
21d, 3ꢀoxadiazolyl
21e, 5ꢀ(2ꢀNꢀ
methyl)tetrazolyl
21f, 5ꢀoxazolyl
21g, 2ꢀfuranyl
21h, 2ꢀtriazolyl
2, Nintedanib
NA
NA
200
62
44
170
NA
NA
27
NA
NA
34
4.0
4.6
4.9
130
110
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
4.5
5.3
13.0
270
15
61
34
12
1.5
1.8
8.0
9.3
1.9
3.1
NA
NA
NA
85
NA
NA
NA
2.6
41
NA: not available. The data were presented with two significant figures due to standard experimental error.
However, all tested compounds in this subseries exhibited signifiꢀ
cant toxicity, as evidenced by the lethality of an intravenous injecꢀ
tion of 5 mg/kg of either compound 21c or 21d. Analogs modiꢀ
fied at the Cꢀ6 position might be metabolized into methanoic acidꢀ
ic derivations in vivo, resulting in the observed toxicities.
Table 3. Results of the assessment of the activity (%) of 1 ꢁM
KBPꢀ7018 toward 64 enzymes in a kinase panel compared with
nintedanib (compounds with <80% inhibition are not shown).
% Enzyme Activity*
Nintedanib
KBPꢀ7018
Based on the findings described above, we concluded that KBPꢀ
7018 failed to inhibit FGFR1 and VEGFR2 but exhibited suffiꢀ
cient inhibitory activities against PDGFRβ, revealing a central
role for KBPꢀ7018 in fibrotic tissue. Consequently, we wondered
that KBPꢀ7018 may have a potent on other target kinases that are
involved in regulating fibrosis. Accordingly, we used a 64ꢀ
member kinome panel to test our hypothesis. Kinases were invesꢀ
tigated based on the increased frequency in a kinase panel assay
related to IPF. Among those kinases, KBPꢀ7018 exhibited >80%
inhibition of only 5 enzymes at 1 ꢁM, whereas nintedanib (2)
inhibited 19 enzymes, indicating the high selectivity of KBPꢀ7018
compared with nintedanib (Table 3).
ABL
ALK
96%
FER
90%
96%
97%
97%
84%
100%
95%
100%
92%
RET
99%
91%
87%
91%
88%
92%
91%
96%
83%
85%
99%
99%
89%
100%
FGR
FLT3
FYN
BLK
FLT3
FYN
HCK
RET
BTK
cꢀKIT
INSR
ITK
PDGFRα
cꢀKIT
YES
cꢀSRC
LCK
LYNa
JAK3
PDGFRα
*
Data for the following 45 kinases are not shown: AKT1, AMPKa1, AURA/B,
BRAF, BRK, CDK2, CHK1, CK1d, CSK, DYRK1a, EGFR, EGFR (T790M),
ERK2, GSK3, p70S6K, HER2/4, IGF1R, IKKβ, IRAK1/4, JAK1/2, JNK2/3,
MAPKAPK2/5, cꢀMET, MSK1, MST2, NEK2, P38α/β, p70S6K, PDK1,
PI3Kα/δ, PKCa, cꢀRaf, ROCK2, RSK1, SGK, SYK, ZAP70 (the kinase abbreꢀ
viations shown in Supporting Information).
4
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Table 4. PK properties of KBPꢀ7018.
ed improved PK profiles compared with nintedanib, as supported
1
by its acceptable oral bioavailability and halfꢀlife in all tested
species. In a previous study, KBPꢀ7018 showed a significantly
lower efflux ratio against Pꢀgp than nintedanib in a Cacoꢀ2 cell
monolayer transport system13, thereby increasing intestinal perꢀ
meability and absorption in vivo. Second, KBPꢀ7018 demonstratꢀ
ed a highly selectively inhibition of tyrosine kinases compared
with nintedanib. Specifically, it exhibited a lower affinity for
VEGFR2, a known antiꢀcancer target, resulting in a lower death
rate in the mouse model of BLMꢀinduced pulmonary fibrosis.
Accordingly, KBPꢀ7018 is superior to nintedanib and displays a
wider therapeutic window (Figure 2). Finally, KBPꢀ7018 had a
less profound effect on hERG K, thus reducing the relating cardiꢀ
ac side effect.
2
3
4
5
6
7
8
9
Species
Dose
(mg/kg)
50
10
20
t1/2
(h)
4.3
4.8
3.3
AUC
(h·ng/mL)
17,004
6406
F
(p.o.)
51%
68%
29%
Mouse
Rat
Dog
2964
KBPꢀ7018 was chosen for further in vivo testing because of its
cellular potency, reduced effect on hERG K and attractive selecꢀ
tivity profiles. The PK properties of KBPꢀ7018 were studied in
mice, rats and dogs. The oral bioavailability and the halfꢀlife of
KBPꢀ7018 were acceptable in all three species (Table 4), indicatꢀ
ing its drugꢀlike profile.
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Finally, KBPꢀ7018 was evaluated in a C57 mouse model of bleoꢀ
mycin (BLM)ꢀinduced chronic pulmonary fibrosis using
nintedanib (2) as a positive control (Figure 2)11, 12. All three doses
(10, 30, 100 mg/kg, q.d.) significantly improved the 28ꢀday surꢀ
vival rate in a doseꢀdependent manner. At 30 mg/kg/day, KBPꢀ
7018 showed a higher in vivo efficacy compared to nintedanib.
Notably, after the oral administration of 100 mg/kg/day
nintedanib, the mice exhibited significantly reduced survival
compared with the mice that received the oral administration of
the lower dose of 30 mg/kg/day, indicating a narrow therapeutic
window for nintedanib. In contrast, mice displayed sufficient
tolerance to KBPꢀ7018 at doses ranging from from 10 mg/kg to
100 mg/kg.
Notably, KBPꢀ7018 inhibited cꢀKIT and RET (which are impliꢀ
cated in angiogenesis and fibrosis14, 15) with a potency in the naꢀ
nomolar range (IC50 = 10 nM and 7.6 nM, respectively). Based on
the results from the present study, KBPꢀ7018 shows promising
potency against IPF in a mouse model of BLMꢀinduced pulmoꢀ
nary fibrosis. The superior in vivo activities of KBPꢀ7018 indicate
that the combination of PDGFR, cꢀKIT and RET as potential therꢀ
apeutic targets for IPF.
In conclusion, a novel series of indolinoneꢀbased multiꢀkinase
inhibitors targeting the angiogenesis and fibrosis pathways were
established. KBPꢀ7018 showed sufficient potencies against three
angiogenic kinases (cꢀKIT, PDGFR, and RET). The PK properties
of KBPꢀ7018 in mice, rats and dogs were favorable. In a mouse
model of BLMꢀinduced pulmonary fibrosis, KBPꢀ7018 doseꢀ
dependently improved the 28ꢀday survival rate when administered
q.d. at doses of 10, 30, 100 mg/kg. Therefore, KBPꢀ7018 repreꢀ
sents a novel multiꢀkinase inhibitor with improved activity, high
selectivity, and acceptable PK profiles. KBPꢀ7018 will proceed to
phase I clinical trials in the near future.
100
Sham
Model
90
Nintedanib 100mg/kg, q.d
80
70
60
50
40
Nintedanib 30mg/kg, q.d
**
KBP-7018 100mg/kg, q.d
*
**
KBP-7018 30mg/kg, q.d
KBP-7018 10mg/kg, q.d
*
Log-rank test
*P<0.05
**P<0.01
0
5
10
15
20
25
30
28
Administration day
Figure 2.The efficacy of KBPꢀ7018 in a mouse model of BLMꢀ
induced pulmonary fibrosis. Sham: saline; Model: intratracheally
injection of a BLM solution (5.0 mg/kg in 50 ꢁL)
ASSOCIATED CONTENT
Supporting Information
The improved efficacy of KBPꢀ7018 compared to nintedanib
might be attributed to several aspects. Firstly, KBPꢀ7018 exhibitꢀ
The Supporting Information is available free of charge on the
ACS Publications website at DOI :
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Page 6 of 7
Detailed descriptions of the experiments, in vitro kinase and celluꢀ
5.
Hilberg, F.; Roth, G. J.; Krssak, M.; Kautschitsch,
1
2
3
4
5
6
7
lar activity assays, PK and in vivo animal model and experimental
S.; Sommergruber, W.; Tontsch-Grunt, U.; Garin-Chesa,
P.; Bader, G.; Zoephel, A.; Quant, J.; Heckel, A.; Rettig, W.
J. BIBF 1120: triple angiokinase inhibitor with sustained
receptor blockade and good antitumor efficacy. Cancer
Res 2008, 68, 4774-82.
treatments (PDF) are included in the Supporting Information.
AUTHOR INFORMATION
Corresponding Authors
8
9
6.
Roth, G. J.; Binder, R.; Colbatzky, F.; Dallinger,
*E-mail: liuhongzhuo@syphu.edu.cn (H. Liu)
C.; Schlenker-Herceg, R.; Hilberg, F.; Wollin, S. L.; Kaiser,
R. Nintedanib: from discovery to the clinic. J Med Chem
2015, 58, 1053-63.
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Author Contributions
7.
Macagno, F.; Varone, F.; Leone, P. M.; Mari, P. V.;
The manuscript was written with contributions from all authors.
All authors have approved the final version of the manuscript.
Panico, L.; Berardini, L.; Richeldi, L. New treatment
directions for IPF: current status of ongoing and upcoming
clinical trials. Expert Rev Respir Med 2017, 11, 533-548.
Notes
8.
Hughes, G.; Toellner, H.; Morris, H.; Leonard, C.;
The authors have no competing financial interests to declare.
Chaudhuri, N. Real World Experiences: Pirfenidone and
Nintedanib are Effective and Well Tolerated Treatments
for Idiopathic Pulmonary Fibrosis. J Clin Med 2016, 5.
ABBREVIATIONS
BLM: bleomycin; cꢀKIT: cꢀKit protoꢀoncogene encoded protein
tyrosine kinase; hERG: human etherꢀaꢀgoꢀgo related gene; IPF:
idiopathic pulmonary fibrosis; PDGFRα: plateletꢀderived
growth factor receptor α; Pꢀgp: Pꢀglycoprotein; PK: pharmacokiꢀ
netic; RET: REarranged during Transfection (RET) protoꢀ
oncogene encoded protein tyrosine kinase; SAR: structureꢀactivity
relationship.
9.
Lo, H., Wang, A., Zhang Q. Indole full ketone
derivative used as tyrosine kinase inhibitor.
WO2014/086102 A1 2014.
10.
Treu, M. K., Thomas; Reiser Ulrich.
WO2010/012747A1 2010.
11.
Sato, N.; Takasaka, N.; Yoshida, M.; Tsubouchi,
K.; Minagawa, S.; Araya, J.; Saito, N.; Fujita, Y.; Kurita, Y.;
Kobayashi, K.; Ito, S.; Hara, H.; Kadota, T.; Yanagisawa,
H.; Hashimoto, M.; Utsumi, H.; Wakui, H.; Kojima, J.;
Numata, T.; Kaneko, Y.; Odaka, M.; Morikawa, T.;
Nakayama, K.; Kohrogi, H.; Kuwano, K. Metformin
attenuates lung fibrosis development via NOX4
suppression. Respir Res 2016, 17, 107.
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