Discovery of anilinopyrimidines as dual inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and cellular activity

Article abstract of DOI:10.1021/ml500066m

Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed

Full text of DOI:10.1021/ml500066m

Letter
pubs.acs.org/acsmedchemlett
Discovery of Anilinopyrimidines as Dual Inhibitors of c‑Met and
VEGFR-2: Synthesis, SAR, and Cellular Activity
Zhengsheng Zhan,†,∥ Jing Ai,‡,∥ Qiufeng Liu,§,∥ Yinchun Ji,‡ Tiantian Chen,§ Yechun Xu,*,§
Meiyu Geng,*,‡ and Wenhu Duan*,†
‡
§
†Department of Medicinal Chemistry, Division of Antitumor Pharmacology, and Drug Discovery and Design Center, State Key
Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road,
Shanghai 201203, China
S
* Supporting Information
ABSTRACT: Both c-Met and VEGFR-2 are important targets for cancer therapies. Here
we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an
anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid
analoguing of the designed molecules for structure−activity relationship (SAR)
exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-
2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent
antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33
to 1.7 μM. In addition, a cocrystal structure of c-Met in complex with 3h has been
determined, which reveals the binding mode of c-Met to its inhibitor and helps to
interpret the SAR of the analogues.
KEYWORDS: Anilinopyrimidine, dual inhibitor, c-Met, SAR, VEGFR-2
he receptor tyrosine kinase c-Met and its natural ligand
Thepatocyte growth factor (HGF) generate the c-Met
signaling, which promotes the invasive growth during
embryonic development, wound healing, and oncogenesis.1
Aberrant expression of c-Met/HGF axis has been detected in a
variety of solid tumors.2−5 VEGFR-2 or KDR (kinase insert
domain receptor), a member of vascular endothelial growth
factor receptors (VEGFRs), also belongs to receptor tyrosine
kinase family. Its activation by vascular endothelial growth
factor (VEGF0) promotes several key processes required for
forming new blood vessels.6,7
c-Met has been shown to synergistically collaborate with
VEGFR-2, resulting in promoting angiogenesis of development
and progression of various human cancers.8−10 Therefore,
molecules that simultaneously inhibit c-Met and VEGFR-2 may
be superior to either c-Met-selective or VEGFR-2-selective
inhibitor as they can interrupt multiple signaling pathways
involved in tumor angiogenesis, proliferation, and metastasis.11
Cabozantinib (1 in Figure 1), an approved drug for the
treatment of medullary thyroid cancer, is a highly potent c-Met
and VEGFR-2 inhibitor.12,13 A similar compound, dianilinopyr-
imidine urea 2, was reported only as a potent VEGFR-2
inhibitor with an enzymatic IC50 of 18 nM.14 The difference in
the biological profiles of 1 and 2 implied that the cyclopropane-
1,1-dicarboxamide moiety might be important for the high
inhibition of both c-Met and VEGFR-2 of cabozantinib. On the
basis of this assumption, we first designed and synthesized
compound 3a, which was a hybrid structure containing both
Figure 1. Design of the anilinopyrimidine 3a.
the cyclopropane-1,1-dicarboxamide moiety of cabozantinib
and the anilinopyrimidine core structure of 2 (Figure 1). As
expected, compound 3a potently inhibited both c-Met and
VEGFR-2 with enzymatic IC50 values of 8.8 and 16 nM,
respectively. Encouraged by this promising result, we prepared
Received: February 10, 2014
Accepted: March 26, 2014
Published: March 26, 2014
© 2014 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 1. Synthesis of Compounds 3a−f, 3h−r, 10b, and 11
a
Reagents and conditions: (a) p-toluene sulfonic acid monohydrate, DMF, 90 °C for 6a, 6b, and 6d/microwave at 80 °C for 6c; (b) Fe, NH4Cl,
EtOH/H2O, reflux; (c) SOCl2, Et3N, THF, then aniline or substituted aniline; (d) EDCI, DMF.
a
Scheme 2. Synthesis of Compounds 3g, 10a, and 10c−n
a
Reagents and conditions: (a) 9b, EDCI, DMF; (b) 2,4-dichloropyrimidine, K2CO3, DMF, 80 °C; (c) R’NH2, Xantphos, Pd2(dba)3, Cs2CO3, 1,4-
dioxane, 80 °C; (d) RNH2, Et3N, THF, 80 °C.
a series of compounds bearing an anilinopyrimidine scaffold to
explore their structure−activity relationships (SARs).
and 18a−d. Buchwald−Hartwig reaction of chloro compounds
14a−f with various arylamines provided 3g, 10a, 10c−l, 16a,
16b, 18a, and 18b. However, analogues 10m and 10n were
easily prepared from chloro compound 14b with aliphatic
amines through SNAr displacement.
The compounds depicted in Tables 1−3 were assayed with
the enzymatic activities against c-Met and VEGFR-2, using
PF234106615 and AP2453416 as comparison. The SARs of the
analogues with the varied substitutions at A and B rings (Table
1) were first discussed. On the B ring, among the series of para-
fluoro, bromo, chloro, methyl, trifluoromethyl substituted
To achieve a rapid structure−activity relationship (SAR)
exploration, two efficient synthetic routes were employed for
preparation of the analogues. Scheme 1 illustrates the synthesis
of 3a−f, 3h−r, 10b, and 11. Intermediates 7a−d were prepared
through an acid-catalyzed displacement of chloro compounds
5a and 5b with anilines 4a−4c followed by a reduction reaction
with iron powder. The condensation of 7a−d with carboxylic
acids 9a−n afforded 3a−f, 3h−r, 10b, and 11. Schemes 2 and 3
outline the synthesis of analogues 3g, 10a, 10c−n, 16a, 16b,
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 3. Synthesis of Compounds 16a, 16b, and 18a−d
a
Reagents and conditions: (a) 13b, K2CO3, DMF, 80 °C; (b) 4a, Xantphos, Pd2(dba)3, Cs2CO3, 1,4-dioxane, 80 °C; (c) 12b, KOtBu, DMA, 80 °C;
(d) 9b, EDCI, DMF; (e) urea hydrogen peroxide, K2CO3, acetone/H2O; (f) NaOH, NaClO, i-PrOH/H2O.
a
to 2-fluoro substitution. X-ray crystallography of c-Met and 3h
(Figure 2) showed that the hydrophobic pocket where the A
ring was accommodated did not tolerate bulky substituents;
therefore, no further modification was carried out on the A ring.
Table 1. SAR of A and B Rings
b
IC50 (nM)
Compd R1
R2
VEGFR-2
16.0 4.0
c-Met
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
H
8.8 1.4
p-F
p-Cl
p-Br
14.0 2.0
30.3 4.2
61.5 8.9
54.0 15.5
219.9 70.3
4.0 0.5
7.9 0.4
32.5 2.1
66.4 11.2
18.6 4.6
p-CH3
p-CF3
184.0 34.8
13.1 1.6
3g
3h
3i
2-F p-F
3-F p-F
6.0 1.0
6.7 0.7
Figure 2. Cocrystal structure of the compound 3h in complex with the
kinase domain of c-Met. The pdb code of the structure is 4MXC. (A)
An overview of the complex structure. The molecular surface of 3h
buried into the kinase domain is represented by dots, and the
compound is shown by sticks. (B) The hydrogen bond interactions
(dash lines) as well as the π−π stacking interactions between 3h and
residues of c-Met.
3-F p-Br
46.6 5.9
6.1 1.6
70.6 0.9
3j
3-F p-OCH3
3-F m-OCH3
3-F m-CH3
337.6 4.1
683.1 58.0
81.9 16.9
25.8 7.7
3k
3l
5.6 0.1
42.7% @ 10 μM
12.7 2.8
43.0 7.0
9.8 0.3
3m
3n
3o
3p
3q
3r
3-F
H
3-F m-F
155.1 19.4
212.7 9.7
234.3 22.2
791.9 169.2
17.7% @ 10 μM
3-F m-Cl
3-F m-CF3
3-F m-CF3, p-Cl
48.0 8.0
83.6 0.9
44.5 7.5
With optimized A and B rings, we then investigated SARs on
the 2-position of the pyrimidine of 3h (Table 2). The para- and
ortho-methylsulfonylmethyl analogues (10a and 10b) displayed
a lower potency than their meta-substituted counterpart 3h in
both VEGFR-2 and c-Met, indicating that meta substitution is
preferred in this series of compounds. Compound 10e was
prepared to test the impact of removal of the methylsulfo-
nylmethyl on its activity, and the result showed that this
modification led to a sharp drop in potency on both c-Met and
VEGFR-2. The drop in potency can be explained by the fact
that the hydrogen bond between the methylsulfonyl oxygen
and the backbone NH of Asp 1164 was essential for
maintaining c-Met potency as was confirmed by the crystal
structure of c-Met and 3h (Figure 2B). To examine the role of
NH in the anilinopyrimidine moiety on the activity, we
3-F m-CF3,
p-CN
a
See Supporting Information for a description of the assay conditions.
b
c-Met IC50 of PF2341066 = 1.5
AP24534 = 4.3 0.4 nM.
0.3 nM; VEGFR-2 IC50 of
analogues (3b−3f), the activity of para-fluoro analogue 3b was
equipotent to that of 3a on both c-Met and VEGFR-2, and the
other substituents led to a substantial drop in potency on both
c-Met and VEGFR-2. Substitution patterns on the B ring of 3h
revealed that c-Met was more sensitive to bulky substituents
(3i−k, and 3o−r). On the A ring, the 3-fluoro analogue 3h
displayed a better enzymatic potency than the 2-fluoro
analogue 3g, suggesting that 3-fluoro substitution is superior
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ACS Medicinal Chemistry Letters
Letter
a
tuted pyridine analogue were also explored (Table 3). The
result showed that the 4,6-disubstituted pyrimidine analogues
Table 2. SAR of 2-Substituents on the Pyrimidine Ring
a
Table 3. SAR of Pyrimidine Derivatives
b
IC50 (nM)
Compd
R
X
VEGFR-2
6.0 1.0
c-Met
6.7 0.7
3h
16a
16b
18a
18b
18c
18d
H
N
55.0 13.0
21.7 1.0
CH3
H
N
37.4% @ 10 μM
16.0 3.0
924.0 9.8
3.8 0.5
CH
CH
CH
CH
CN
0 @ 10 μM
3.1% @ 10 μM
0 @ 10 μM
805.8 98.1
211.1 67.2
39.6% @ 10 μM
CONH2
NH2
a
See Supporting Information for a description of the assay conditions.
b
c-Met IC50 of PF2341066 = 1.5
0.3 nM; VEGFR-2 IC50 of
AP24534 = 4.3 0.4 nM.
(16a and 16b) exhibited decreased c-Met and VEGFR-2
potencies and that the pyridine analogue 18a inhibited c-Met
with an IC50 value of 3.8 nM, a moderate improvement
compared to 3h. The crystal of 3h in complex with the kinase
domain of c-Met revealed that 3h occupied the ATP-binding
site as well as an adjacent pocket of the kinase domain and
trapped the kinase in its inactive conformation (Figure 2A).17
The details of the hydrogen bonds were shown in Figure 2B. In
particular, a π−π stacking interaction occurred between the
phenyl ring of Phe1223 and the central fluorophenyl group of
3h, which dislodges Phe1223 of the DFG motif from its
activated conformation.17
The cellular assays commenced by testing the activities of the
compounds with good enzymatic potencies (3a, 3b, 3g, 3h, and
18a) in MKN-45 gastric carcinoma cells. As shown in Table 4,
Table 4. Effects of Selected Analogues on Human Cancer
a
Cell Proliferation
a
See Supporting Information for a description of the assay conditions.
b
IC50 (μM)
c-Met IC50 of PF2341066 = 1.5
AP24534 = 4.3 0.4 nM.
0.3 nM; VEGFR-2 IC50 of
Compd
MKN-45
EBC-1
3a
1.7 0.04
1.3 0.28
0.59 0.04
1.1 0.05
0.46 0.001
prepared an N-methylated analogue 11, but it was inactive
against both c-Met and VEGFR-2. The loss of potency might
be attributed to the loss of the hydrogen bond between NH
and the backbone carbonyl oxygen of Met 1160 in the hinge
region as shown in Figure 2B. Variations of substituents on the
2-position of pyrimidine were then examined. Much to our
disappointment, substitution of meta-methylsulfonylmethyl-
phenyl with methylsulfonylmethylpyrazolyl (10d), acetylphenyl
(10f), nitrophenyl (10g and 10h), trifluoromethylphenyl (10k
and 10l), and two alkyl (10m and 10n) ended up with poor
potencies in both c-Met and VEGFR-2. Therefore, we
concluded that both the 3-methylsulfonylmethylaniline and
N-(3-fluoro-phenyl)-N′-(4-fluoro-phenyl)cyclopropane-1,1-di-
carboxamide moieties were crucial to the analogues for good
potencies on both c-Met and VEGFR-2 as shown by the data in
Tables 1 and 2.
3b
3g
0.72 0.04
0.33 0.01
3h
18a
a
See Supporting Information for a description of the assay conditions.
compounds 3g and 18a outperformed the other counterparts
with IC50 values of 0.59 and 0.46 μM, respectively. Moreover,
3g and 18a also demonstrated strong inhibition in EBC-1
(human nonsmall-cell lung cancer cell line) cells, though the
assayed compounds suffered a decrease in enzyme-to-cell shift,
which might be ascribed to the poor cellular penetration. In an
immunoblot analysis of compound 3g or 18a treated EBC-1
cells, complete inhibition of c-Met phosphorylation was
observed at a concentration of 0.5 μM (Figure 3). In addition,
c-Met downstream signaling molecules (Erk 1/2 and AKT)
were also significantly suppressed.18 These data suggest that
As an extension of the 2,4-disubstitued pyrimidine chemo-
type, 4,6-disubstituted pyrimidine analogues and 2,4-disubsti-
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Notes
The authors declare no competing financial interest.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures and analytical data for compounds
reported in this letter, procedures for enzymatic and cellular
assays, and procedures for X-ray cocrystallization. This material
is available free of charge via the Internet at http://pubs.acs.org.
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D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y.-C.; Joly, A. H. Cabozantinib
(XL184), a novel MET and VEGFR2 inhibitor, simultaneously
suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer
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AUTHOR INFORMATION
Corresponding Authors
*(W.D.) E-mail: whduan@simm.ac.cn. Phone: +86-21-
50806032.
■
(13) Kurzrock, R.; Sherman, S. I.; Ball, D. W.; Forastiere, A. A.;
Cohen, R. B.; Mehra, R.; Pfister, D. G.; Cohen, E. E. W.; Janisch, L.;
Nauling, F.; Hong, D. S.; Ng, C. S.; Ye, L.; Gagel, R. F.; Frye, J.;
*(M.G.) E-mail: mygeng@simm.ac.cn.
*(Y.X.) E-mail: ycxu@simm.ac.cn.
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∥(Z.Z., J.A., and Q.L.) These authors contributed equally to this
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Funding
We thank the National Natural Science Foundation of China
(no. 81273365 and 81102461), Major Projects in National
Science and Technology of China (no. 2010ZX09401-401,
2012ZX09103101-024, and 2012ZX09301001-007), National
Program on Key Basic Research Project of China
(2012CB910704), and the ″100 Talents Project″ of CAS (to
Y.X.) for their financial support.
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