Discovery of a new series of naphthamides as potent VEGFR-2 kinase inhibitors

Article abstract of DOI:10.1021/ml5000417

Inhibition of VEGFR-2 signaling pathway has already become one of the most promising approaches for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of a new series of naphthamides as potent inhibitors of VEGFR-2. Among these compounds, 14c exhibited high VEGFR-2 inhibitory potency in both enzymatic and HUVEC cellular proliferation assays, with IC₅₀ values of 1.5 and 0.9 nM, respectively. Kinase selectivity profiling revealed that 14c was a multitargeted inhibitor, and it also exhibited good potency against VEGFR-1, PDGFR-β, and RET. Furthermore, 14c effectively blocked tube formation of HUVEC at nanomolar level. Overall, 14c might be a promising candidate for the treatment of cancer.

Full text of DOI:10.1021/ml5000417

Letter
pubs.acs.org/acsmedchemlett
Discovery of a New Series of Naphthamides as Potent VEGFR‑2
Kinase Inhibitors
Yongcong Lv,†,∇ Mengyuan Li,‡,§,⊥,∇ Ting Liu,†,∥,○ Linjiang Tong,‡ Ting Peng,‡ Lixin Wei,§ Jian Ding,‡
Hua Xie,*,‡ and Wenhu Duan*,†
†Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road,
Shanghai 201203, China
‡Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
§Northwest Institute of Plateau Biology, Chinese Academy of Sciences, 23 Xinning Road, Qinghai 81008, China
∥Medical College of Nanchang University, 461 Bayi Road, Nanchang, Jiangxi 330066, China
S
* Supporting Information
ABSTRACT: Inhibition of VEGFR-2 signaling pathway has already become one of the
most promising approaches for the treatment of cancer. In this study, we describe the
design, synthesis, and biological evaluation of a new series of naphthamides as potent
inhibitors of VEGFR-2. Among these compounds, 14c exhibited high VEGFR-2
inhibitory potency in both enzymatic and HUVEC cellular proliferation assays, with
IC50 values of 1.5 and 0.9 nM, respectively. Kinase selectivity profiling revealed that 14c
was a multitargeted inhibitor, and it also exhibited good potency against VEGFR-1,
PDGFR-β, and RET. Furthermore, 14c effectively blocked tube formation of HUVEC at
nanomolar level. Overall, 14c might be a promising candidate for the treatment of
cancer.
KEYWORDS: Angiogenesis, HUVEC, inhibitor, naphthamide, VEGFR-2
ngiogenesis, the formation of new blood vessels from pre-
existing vasculature, is essential for both embryonic
axitinib,15 vandetanib,16 and regorafenib17) targeting VEGFR-
2 and/or other kinases have been approved for the treatment of
cancers, such as advanced renal cell carcinoma (RCC) and
hepatocellular carcinoma (HCC). In this communication, we
report the design, synthesis, and biological evaluation of a new
series of naphthamides as potent VEGFR-2 inhibitors (Figure
1).
Linifanib (1) (ABT869, Figure 1), a multitargeted RTK
inhibitor bearing an N,N′-diaryl urea moiety, is a potent
VEGFR-2 inhibitor (IC50 = 4 nM). It also inhibits other kinases
such as VEGFR-1 (Flt-1), Flt-3, Kit, and PDGFR-β with IC50
values of 3, 4, 14, and 66 nM, respectively. It is currently in
phase III clinical trials for the treatment of advanced HCC.18 In
2008, Amgen Inc. researchers reported a series of naphtha-
mides19 and 2,3-dihydro-1,4-benzoxazines20 as potent VEGFR
inhibitors. Of naphthamides, representative compound 2
(Figure 1) showed IC50 values of 0.5 and 8 nM for VEGFR-
2 and VEGF-induced proliferation of human umbilical vein
endothelial cells (HUVEC), respectively. In benzoxazine series,
A
growth and normal physiological processes, such as reproduc-
tion and wound healing.1,2 Aberrant angiogenesis has been
observed in a wide range of diseases including atherosclerosis,
retinopathies, endometriosis, arthritis, and cancer.3 As angio-
genesis plays an important role in the process of tumor growth
and metastasis, it has been proved in humans that restricting
the blood supply could limit the growth of a solid tumor.4
Many factors are involved in tumor angiogenesis, among
which the vascular endothelial growth factors (VEGFs) play a
major role.5 Overactivation of vascular endothelial growth
factor receptors (VEGFRs), especially VEGFR-2, is closely
related to poor prognosis and metastasis in the majority of solid
tumor patients.6,7 The VEGF-mediated VEGFR-2 signaling
promotes several endothelial responses required for the
formation of new blood vessels, such as cell proliferation,
migration, and survival.8
As VEGFR-2 signaling is important in tumor angiogenesis,
blocking VEGFR-2 signaling pathway has become an attractive
approach for the treatment of cancers. Receptor tyrosine kinase
(RTK) inhibitors that target VEGFR-2 have been demon-
strated to possess substantial antitumor activity, and generally
they are ATP-competitive small molecule inhibitors.9−11 In fact,
six such inhibitors (sorafenib,12 sunitinib,13 pazopanib,14
Received: January 29, 2014
Accepted: February 24, 2014
Published: February 24, 2014
© 2014 American Chemical Society
592
dx.doi.org/10.1021/ml5000417 | ACS Med. Chem. Lett. 2014, 5, 592−597

ACS Medicinal Chemistry Letters
Letter
Figure 1. Design of hybrid compounds 4a and 5.
a
Scheme 1. Synthesis of Indazolylnaphthamides 4a−v
a
Reagents and conditions: (a) SOCl2, MeOH, reflux, 99%; (b) Tf2O, DIPEA, DCM, −78 °C, 93%; (c) Pd(dppf)Cl2, dppf, AcOK, bis(pinacolato)-
diboron, dioxane, 80 °C, 98%; (d) LiOH, H2O, THF, rt, 78%; (e) RNH2, EDCI, DMAP, DCM, 0 °C to rt, 21−68%; (f) Pd(PPh3)2Cl2, Na2CO3,
EtOH, toluene, H2O, 85 °C, 38−80%.
compound 3 (Figure 1) showed IC50 values of 0.5 and 4 nM for
VEGFR-2 and HUVEC, respectively.
carbonyl and the backbone amide NH of Asp1046; and finally
the urea external NH and Glu885 carboxylate.18 Compounds 2
and 3 have similar interaction patterns with VEGFR-2: both
bind to the ATP binding site in the DFG-out conformation,
enabling the p-chlorophenyl to penetrate into the extended
hydrophobic pocket; the nitrogen of the quinoline forms a
hydrogen bond with the backbone amide NH of Cys919; the
carbonyl oxygen and the amide NH in compound 2 or the urea
NH in compound 3 form two hydrogen bonds with the
backbone amide NH of Asp1046 and the side chain of Glu885,
respectively.19,20 As the N,N′-diaryl urea moiety of 1, the
Linifanib binds to the ATP binding site of VEGFR-2 and
forces the protein to adopt a DFG-out conformation.18 This
conformation is incompatible with ATP binding, enabling an
appropriately substituted inhibitor to penetrate into the
extended hydrophobic pocket.21 Linifanib forms several
hydrogen bonds with the amino acid residues in the catalytic
site of VEGFR-2: in the hinge region, the 3-amino group on the
indazole and the backbone carbonyl of Glu917, the ring N2
nitrogen, and the backbone amide NH of Cys919; the urea
593
dx.doi.org/10.1021/ml5000417 | ACS Med. Chem. Lett. 2014, 5, 592−597

ACS Medicinal Chemistry Letters
Letter
a
naphthamide moiety of 2, and the urea moiety of 3 occupy
similar areas of kinase region, forming two hydrogen bonds
with Asp1046 and Glu885, we envisioned that cyclization of 1
to the corresponding naphthamide or 2,3-dihydro-1,4-benzox-
azine may form new VEGFR-2 inhibitor scaffolds. To test the
hypothesis, naphthamide 4a and 2,3-dihydro-1,4-benzoxazine 5
(Figure 1) were prepared, and the enzymatic assay showed that
both 4a and 5 were potent VEGFR-2 inhibitors with IC50
values of 1.6 and 40.8 nM, respectively. Encouraged by the high
potency of 4a, we chose 4a as the lead molecule for further
structure−activity relationship (SAR) exploration.
Scheme 3. Synthesis of 2,3-Dihydro-1,4-benzoxazine 5
The general synthetic strategy for indazolylnaphthamides
4a−v is outlined in Scheme 1. Triflate 8 was synthesized in two
steps starting with the conversion of the 6-hydroxy-1-naphthoic
acid 6 to the corresponding methyl ester 7 followed by
triflation in the presence of DIPEA.19 Palladium-catalyzed
coupling of the triflate 8 with bis(pinacolato)-diboron afforded
the naphthylborate 9, which was then hydrolyzed to the
carboxylic acid 10. Treatment of 10 with the corresponding
amines in the presence of EDCI and DMAP gave naphthamides
11a−v. Preparation of 4a−v was achieved by Suzuki coupling
between 4-iodo-1H-indazol-3-amine 12 and 11a−v. Derivatives
14a−c were similarly prepared by using a coupling reaction of
11a with corresponding heteroaryl bromides 13a−c (Scheme
2).
a
Reagents and conditions: (a) Fe, NH4Cl, EtOH, H2O, 70 °C, 70%;
(b) chloroacetyl chloride, Cs2CO3, MeCN, rt, 82%; (c) BH3·THF,
THF, reflux, 96%; (d) Pd(dppf)Cl2, AcOK, bis(pinacolato)-diboron,
dioxane, 110 °C, 55%; (e) PhNCO, Et3N, DCM, rt, 95%; (f)
Pd(PPh3)2Cl2, Na2CO3, EtOH, toluene, H2O, 85 °C, 30%.
a
Table 1. Biological Activity of Compounds 4a and 5
a
Scheme 2. Synthesis of Naphthamides 14a−c
a
Reagents and conditions: Pd(PPh3)2Cl2, Na2CO3, EtOH, toluene,
H2O, 85 °C, 69−81%.
The synthesis of 5 is illustrated in Scheme 3. Reduction of 5-
bromo-2-nitrophenol 15 followed by cyclization gave 17, which
was then reduced to benzoxazine 18. The palladium-catalyzed
coupling of 18 with bis(pinacolato)-diboron afforded the borate
19, which was reacted with phenyl isocyanate to provide 20.
Finally, coupling 20 with iodide 12 afforded 5.
All compounds depicted in Tables 1−3 were evaluated for
their inhibitory activity against VEGFR-2 and VEGF-induced
proliferation of HUVEC, using linifanib as reference. Starting
with the first two compounds 4a and 5, the biological data
revealed that naphthamide 4a displayed more potent VEGFR-2
inhibition than that of 2,3-dihydro-1,4-benzoxazine 5 (IC50: 1.6
nM for 4a vs 40.8 nM for 5, Table 1). The result was similar in
the further HUVEC cellular assay: 4a exhibited higher cellular
potency than 5 (IC50: 3.8 nM for 4a vs 12.9 nM for 5).
Accordingly, 4a was chosen as the lead molecule for further
SAR exploration.
We first examined the impact of the amide variations on their
biological activity. Table 2 contains derivatives differing in the
substitution patterns of the benzene rings, the isosteres of the
benzene ring, and the types of alkyl groups. Incorporation of a
methyl at ortho-position of the phenyl moiety led to a
significant loss in both enzymatic and cellular potency by
16.7-fold and 22.7-fold, respectively (4b vs 4a). A methyl at the
meta-position also reduced enzymatic potency but improved
a
IC50 values were the mean
SD of two or more independent
b
experiments. Inhibition of VEGF-induced proliferation of human
umbilical vein endothelial cells.
cellular potency by 1.8-fold (4c vs 4a). The para-methyl
analogue 4d showed similar inhibition of the enzyme (IC50
=
1.9 nM) but improved cellular potency (IC50 = 1.3 nM)
compared to 4a. meta-Ethyl substitution (4e) reduced
enzymatic potency by 11.4-fold but improved cellular potency
by 2.7-fold (4e vs 4a). Besides, meta-trifluoromethyl analogue
4f showed the same enzymatic potency (IC50 = 7.3 nM) but a
drastically decreased cellular potency (IC50 > 100 nM)
compared to 4c. Incorporation of an additional fluorine atom
at the para-position to the methyl on the phenyl in 4c provided
a 2-fold improvement in enzymatic potency accompanied by a
3-fold reduction in cellular potency (4g vs 4c). However,
placing an additional fluorine atom on the phenyl of 4d made
the molecule less active in both enzymatic and cellular assays
(4h and 4i). In halogen-containing analogues 4j−r, no
improvement was observed in the enzymatic assay compared
to 4a, while compounds 4k, 4m, 4n, and 4o showed a slightly
improved cellular potency (IC50 = 2.3, 2.6, 1.6, and 3.1 nM,
respectively). Isostere replacement of the amide benzene ring
594
dx.doi.org/10.1021/ml5000417 | ACS Med. Chem. Lett. 2014, 5, 592−597

ACS Medicinal Chemistry Letters
Letter
a
Table 2. Variations of the Naphthamide
Table 3. Investigation of the Heterocycle Binding to the
a
Hinge Region
b
VEGFR-2 IC50
(nM)
HUVEC IC50
compd
R
(nM)
4a
4b
4c
Ph
1.6 0.5
26.7 1.4
7.3 0.1
1.9 0.4
18.2 2.8
7.3 0.4
3.8 1.0
7.6 0.2
4.5 0.7
18.7 0.7
7.1 0.3
9.2 0.2
92.5 5.9
10.8 2.6
48.4 4.2
24.0 4.2
1.4 0.7
2.5 0.3
9.7 0.2
20.2 0.3
101.3 29.0
95.2 5.7
6.2 1.8
3.8 0.4
86.4 3.5
2.1 0.5
1.3 0.3
1.4 0.4
>100
2-Me-Ph
3-Me-Ph
4-Me-Ph
3-Et-Ph
3-CF3-Ph
4d
4e
4f
4g
2-F-5-Me-Ph
2-F-4-Me-Ph
3-F-4-Me-Ph
2-F-Ph
6.1 0.7
3.3 0.9
4.5 1.7
6.1 0.9
2.3 0.1
17.0 2.4
2.6 0.5
1.6 0.4
3.1 1.3
3.9 0.9
>100
4h
4i
4j
4k
4l
3-F-Ph
4-F-Ph
4m
4n
4o
4p
4q
4r
2,4-F-Ph
3,5-F-Ph
3-Cl-Ph
a
IC50 values were the mean
SD of two or more independent
3-Br-Ph
b
experiments. Inhibition of VEGF-induced proliferation of human
umbilical vein endothelial cells.
3,5-Cl-Ph
3,5-Br-Ph
5-methyl-3-isoxazolyl
3-pyridyl
>100
4s
5.7 0.4
a
c
Table 4. Enzyme Selectivity Profile of 14c
4t
ND
4u
4v
ethyl
7.0 1.0
2.8 0.7
2.3 0.3
enzyme
IC50 (nM)
enzyme
IC50 (nM)
cyclopropyl
VEGFR-1
VEGFR-2
Flt-3
35.1
ErbB2
ErbB4
>10000
>10000
>10000
linifanib
1.5
a
IC50 values were the mean
SD of two or more independent
>10000
548.6
4.6
EGFR (T790M/L858R)
b
experiments. Inhibition of VEGF-induced proliferation of human
umbilical vein endothelial cells. ND: not determined.
PDGFR-α
PDGFR-β
RET
c
c-Src
>10000
>10000
>10000
>10000
20.2
ABl
FGFR-1
EGFR
643.7
>10000
EPH-A2
IGF-1R
proved to be tolerable. In fact, isoxazole derivative 4s exhibited
high enzymatic and cellular activities (IC50 = 9.7 and 5.7 nM,
respectively), which was comparable to the phenyl derivatives.
To further explore the variations of amide moiety, two
derivatives in which phenyls were replaced with ethyl or
cyclopropyl groups were prepared (4u and 4v). These two
compounds showed poor inhibitory activity in VEGFR-2
enzymatic assay (IC50: 101.3 nM for 4u; 95.2 nM for 4v),
while exhibiting low nanomolar inhibition in the cellular assay
(IC50: 7.0 nM for 4u; 2.8 nM for 4v). We speculated that, in
addition to VEGFR-2, 4u and 4v might work on other
anticancer targets in HUVEC; therefore, they performed better
in a cellular system than in enzymatic system.
Next, we tested the influence of the replacement of indazole
moiety with other heterobicycles on their activity. This
modification led to derivatives 14a−c as shown in Table 3.
Compared with 4a, 4-aminofuro[3,2-c]pyridine derivative 14a
and 4-aminothieno[3,2-c]pyridine 14b displayed a 4.4-fold
reduction in enzymatic potency (IC50 = 1.6 vs 7.0 and 7.1 nM)
and a 5.4-fold reduction in cellular potency (IC50 = 3.8 vs 20.5
and 20.2 nM) while 4-aminothieno[2,3-d]pyrimidine derivative
14c exhibited matched enzymatic potency (IC50 = 1.5 nM) but
improved cellular potency (IC50 = 0.9 nM).
a
IC50 values were means of two or more independent experiments.
addition to VEGFR-2, PDGFR-β is also an important
anticancer target through antiangiogenic pathway.22 Therefore,
inhibiting VEGFR-2 and PDGFR-β simultaneously may be
beneficial for antiangiogenic tumor therapy. However, 14c
displayed high selectivity over PDGFR-α (365-fold, IC50
=
548.6 nM) and FGFR-1 (429-fold, IC50 = 643.7 nM) and
excellent selectivity (>6666-fold) over Flt-3, EGFR, ErbB2,
ErbB4, EGFR (T790M/L858R), c-Src, ABl, EPH-A2, and IGF-
1R.
We finally investigated the in vitro antiangiogenic activity of
compound 14c in a tube formation assay. HUVEC were placed
on growth factor reduced matrigel and cultured with different
concentration of 14c in the presence of VEGF. As shown in
Figure 2, compound 14c effectively inhibited endothelial cell
tube formation induced by VEGF in a concentration-dependent
manner, and tube formation was significantly inhibited by 10
nM of 14c.
In conclusion, we report the design, synthesis, and biological
evaluation of novel naphthamides as a new class of VEGFR-2
inhibitors. The hybrid compound 4a served as a starting point
for SAR exploration. SAR studies demonstrated that this new
scaffold was tolerable to most of the modifications, such as
isostere replacement of indazole and benzene and various
To assess the selectivity of this class of derivatives,
compound 14c was profiled against a panel of tyrosine kinases.
As shown in Table 4, 14c exhibited strong potency against
VEGFR-1, PDGFR-β, and RET, with IC50 values of 35.1, 4.6,
and 20.2 nM, respectively. It is worth mentioning that, in
595
dx.doi.org/10.1021/ml5000417 | ACS Med. Chem. Lett. 2014, 5, 592−597

ACS Medicinal Chemistry Letters
Letter
Author Contributions
∇(Y.L. and M.L.) These authors contributed equally to this
work. All authors have given approval to the final version of the
manuscript.
Funding
We thank the National Natural Science Foundation of China
(No. 81273365, 81173080), Major Projects in National Science
and Technology “Creation of Major New Drugs” (no.
2012ZX09103101−024), and the Shanghai Science and
Technology Commission (no. 11431921100 and
12DZ1930802) for their financial support.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
VEGF, vascular endothelial growth factor; VEGFR, vascular
endothelial growth factor receptor; RTK, receptor tyrosine
kinase; ATP, adenosine triphosphate; RCC, renal cell
carcinoma; HCC, hepatocellular carcinoma; Flt, fms-like
tyrosine kinase receptor; KIT, stem cell factor receptor;
PDGFR, platelet-derived growth factor receptor; HUVEC,
human umbilical vein endothelial cells; DFG, highly conserved
triad Asp-Phe-Gly; SAR, structure−activity relationship;
DIPEA, ethyldiisopropylamine; EDCI, 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride; DMAP, 4-dimethy-
laminopyridine; RET, rearranged during transfection; FGFR-1,
fibroblast growth factor receptor 1; EGFR, epidermal growth
factor receptor; ErbB2, human epidermal growth factor
receptor 2; ErbB4, human epidermal growth factor receptor
4; EGFR (T790M/L858R), EGFR with T790M/L858R
mutations; c-Src, tyrosine kinase encoded by the CSK gene;
ABl, Abelson tyrosine kinase; EPH-A2, ephrin receptor A2;
IGF-1R, insulin-like growth factor 1 receptor
Figure 2. Effect of 14c on VEGF-induced endothelial tube formation.
HUVEC (20,000 cells/well on a 96-well plate) were treated with
different concentration of 14c in the presence of VEGF (100 ng/mL)
after placed on matrigel. Positive control was treated with VEGF alone.
Tube formation was observed by electron microscope at 4×
magnification after incubated at 37 °C for 6 h.
substitution patterns of benzene ring. Privileged compound 14c
exhibited high potency in both enzymatic and cellular assays.
Kinase selectivity studies revealed that, in addition to VEGFR
inhibition, 14c also inhibited PDGFR and RET kinases but
showed high selectivity over other kinases. Moreover, 14c
effectively inhibited angiogenesis in HUVEC tube formation
assay. Therefore, our hybrid design of new VEGFR-2 inhibitor
scaffolds and an understanding of their SARs offer promising
opportunities to develop more effective anticancer agents.
REFERENCES
■
(1) Carmeliet, P. Angiogenesis in health and disease. Nat. Med. 2003,
9, 653−660.
(2) Siemann, D. W.; Chaplin, D. J.; Horsman, M. R. Vascular-
targeting therapies for treatment of malignant disease. Cancer 2004,
100, 2491−2499.
(3) Potente, M.; Gerhardt, H.; Carmeliet, P. Basic and therapeutic
aspects of angiogenesis. Cell 2011, 146, 873−887.
(4) Gasparini, G.; Longo, R.; Toi, M.; Ferrara, N. Angiogenic
inhibitors: a new therapeutic strategy in oncology. Nat. Clin. Pract.
Oncol. 2005, 2, 562−577.
ASSOCIATED CONTENT
■
S
* Supporting Information
General synthetic schemes and details of experimental
procedures for the synthesis of all compounds, analytical data,
and biological assay descriptions. This material is available free
of charge via the Internet at http://pubs.acs.org.
(5) Olsson, A. K.; Dimberg, A.; Kreuger, J.; Claesson-Welsh, L.
VEGF receptor signaling: in control of vascular function. Nat. Rev. Mol.
Cell Biol. 2006, 7, 359−371.
(6) Poon, R. T.; Fan, S. T.; Wong, J. Clinical implications of
circulating angiogenic factors in cancer patients. J. Clin. Oncol. 2001,
19, 1207−1225.
AUTHOR INFORMATION
■
(7) Takahashi, Y.; Kitadai, Y.; Bucana, C. D.; Cleary, K. R.; Ellis, L.
M. Expression of vascular endothelial growth factor and its receptor,
KDR, correlates with vascularity, metastasis, and proliferation of
human colon cancer. Cancer Res. 1995, 55, 3964−3968.
(8) Holmes, K.; Roberts, O. L.; Thomas, A. M.; Cross, M. J. Vascular
endothelial growth factor receptor-2: structure, function, intracellular
signalling and therapeutic inhibition. Cell Signaling 2007, 19, 2003−
2012.
(9) Schenone, S.; Bondavalli, F.; Botta, M. Antiangiogenic agents: an
update on small molecule VEGFR inhibitors. Curr. Med. Chem. 2007,
14, 2495−2516.
(10) Zhong, H.; Bowen, J. P. Recent advances in small molecule
inhibitors of VEGFR and EGFR signaling pathways. Curr. Top. Med.
Chem. 2011, 11, 1571−1590.
Corresponding Authors
*(W.D.) E-mail: whduan@simm.ac.cn. Phone: +86 21
50806032.
*(H.X.) E-mail: hxie@simm.ac.cn. Phone: +86 21 50805897.
Present Addresses
⊥(M.L.) Division of Anti-Tumor Pharmacology, State Key
Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi
Road, Shanghai 201203, China.
○(T.L.) Department of Medicinal Chemistry, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences,
555 Zu Chong Zhi Road, Shanghai 201203, China.
596
dx.doi.org/10.1021/ml5000417 | ACS Med. Chem. Lett. 2014, 5, 592−597

ACS Medicinal Chemistry Letters
Letter
(11) Musumeci, F.; Radi, M.; Brullo, C.; Schenone, S. Vascular
endothelial growth factor (VEGF) receptors: drugs and new inhibitors.
J. Med. Chem. 2012, 55, 10797−10822.
(12) Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.;
Smith, R. A.; Schwartz, B.; Simantov, R.; Kelley, S. Discovery and
development of sorafenib: a multikinase inhibitor for treating cancer.
Nat. Rev. Drug Discovery 2006, 5, 835−844.
(13) Motzer, R. J.; Michaelson, M. D.; Redman, B. G.; Hudes, G. R.;
Wilding, G.; Figlin, R. A.; Ginsberg, M. S.; Kim, S. T.; Baum, C. M.;
DePrimo, S. E.; Li, J. Z.; Bello, C. L.; Theuer, C. P.; George, D. J.; Rini,
B. I. Activity of SU11248, a multitargeted inhibitor of vascular
endothelial growth factor receptor and platelet-derived growth factor
receptor, in patients with metastatic renal cell carcinoma. J. Clin. Oncol.
2006, 24, 16−24.
(14) Harris, P. A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R. M.;
Davis-Ward, R. G.; Epperly, A. H.; Hinkle, K. W.; Hunter, R. N., III;
Johnson, J. H.; Knick, V. B.; Laudeman, C. P.; Luttrell, D. K.; Mook, R.
A.; Nolte, R. T.; Rudolph, S. K.; Szewczyk, J. R.; Truesdale, A. T.; Veal,
J. M.; Wang, L.; Stafford, J. A. Discovery of 5-[[4-[(2,3-dimethyl-2H-
indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzene-
sulfonamide (pazopanib), a novel and potent vascular endothelial
growth factor receptor inhibitor. J. Med. Chem. 2008, 51, 4632−4640.
(15) Ho, T. H.; Jonasch, E. Axitinib in the treatment of metastatic
renal cell carcinoma. Future Oncol. 2011, 7, 1247−1253.
(16) Commander, H.; Whiteside, G.; Perry, C. Vandetanib: first
global approval. Drugs 2011, 71, 1355−1365.
(17) Strumberg, D.; Scheulen, M. E.; Schultheis, B.; Richly, H.; Frost,
A.; Buchert, M.; Christensen, O.; Jeffers, M.; Heinig, R.; Boix, O.;
̈
Mross, K. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a
phase I study. Br. J. Cancer 2012, 106, 1722−1727.
(18) Dai, Y.; Hartandi, K.; Ji, Z.; Ahmed, A. A.; Albert, D. H.; Bauch,
J. L.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A.; Glaser, K. B.; Harris,
C. M.; Hickman, D.; Guo, J.; Li, J.; Marcotte, P. A.; Marsh, K. C.;
Moskey, M. D.; Martin, R. L.; Olson, A. M.; Osterling, D. J.; Pease, L.
J.; Soni, N. B.; Stewart, K. D.; Stoll, V. S.; Tapang, P.; Reuter, D. R.;
Davidsen, S. K.; Michaelides, M. R. Discovery of N-(4-(3-amino-1H-
indazol-4-yl)phenyl)-N′-(2-fluoro-5-methylphenyl)urea (ABT-869), a
3-aminoindazole-based orally active multitargeted receptor tyrosine
kinase inhibitor. J. Med. Chem. 2007, 50, 1584−1597.
(19) Harmange, J. C.; Weiss, M. M.; Germain, J.; Polverino, A. J.;
Borg, G.; Bready, J.; Chen, D.; Choquette, D.; Coxon, A.; DeMelfi, T.;
DiPietro, L.; Doerr, N.; Estrada, J.; Flynn, J.; Graceffa, R. F.; Harriman,
S. P.; Kaufman, S.; La, D. S.; Long, A.; Martin, M. W.; Neervannan, S.;
Patel, V. F.; Potashman, M.; Regal, K.; Roveto, P. M.; Schrag, M. L.;
Starnes, C.; Tasker, A.; Teffera, Y.; Wang, L.; White, R. D.;
Whittington, D. A.; Zanon, R. Naphthamides as novel and potent
vascular endothelial growth factor receptor tyrosine kinase inhibitors:
design, synthesis, and evaluation. J. Med. Chem. 2008, 51, 1649−1667.
(20) La, D. S.; Belzile, J.; Bready, J. V.; Coxon, A.; DeMelfi, T.;
Doerr, N.; Estrada, J.; Flynn, J. C.; Flynn, S. R.; Graceffa, R. F.;
Harriman, S. P.; Larrow, J. F.; Long, A. M.; Martin, M. W.; Morrison,
M. J.; Patel, V. F.; Roveto, P. M.; Wang, L.; Weiss, M. M.; Whittington,
D. A.; Teffera, Y.; Zhao, Z.; Polverino, A. J.; Harmange, J. C. Novel
2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable
inhibitors of tumor-driven angiogenesis. J. Med. Chem. 2008, 51,
1695−1705.
(21) Huang, L.; Huang, Z.; Bai, Z.; Xie, R.; Sun, L.; Lin, K.
Development and strategies of VEGFR-2/KDR inhibitors. Future Med.
Chem. 2012, 4, 1839−1852.
(22) Abramsson, A.; Lindblom, P.; Betsholtz, C. Endothelial and
nonendothelial sources of PDGF-B regulate pericyte recruitment and
influence vascular pattern formation in tumors. J. Clin. Invest. 2003,
112, 1142−1151.
597
dx.doi.org/10.1021/ml5000417 | ACS Med. Chem. Lett. 2014, 5, 592−597