Discovery of disubstituted imidazo[4,5- b ]pyridines and purines as potent TrkA inhibitors

Article abstract of DOI:10.1021/ml300074j

Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.

Full text of DOI:10.1021/ml300074j

Letter
pubs.acs.org/acsmedchemlett
Discovery of Disubstituted Imidazo[4,5‑b]pyridines and Purines as
Potent TrkA Inhibitors
,†
,†
†
†
§,∥
Tao Wang,* Michelle L. Lamb,* Michael H. Block, Audrey Molina Davies, Yongxin Han,
†
,⊥
†
§,#
†
†
Ethan Hoffmann ,† Stephanos Ioannidis, John A. Josey, Zhong-Ying Liu, Paul D. Lyne,
§
†
‡
†
§,#
Terry MacIntyre, Peter J. Mohr, Charles A. Omer, Tove Sjogren, Kenneth Thress, Bin Wang,
̈
†
†
†
Haiyun Wang, Dingwei Yu, and Hai-Jun Zhang
†
Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
‡
Discovery Sciences, Innovative Medicines, AstraZeneca, Pepparedsleden S431 83 Mo
§Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301, United States
S Supporting Information
̈
lndal, Sweden
*
ABSTRACT: Trk receptor tyrosine kinases have been
implicated in cancer and pain. A crystal structure of TrkA
with AZ-23 (1a) was obtained, and scaffold hopping resulted
in two 5/6-bicyclic series comprising either imidazo[4,5-
b]pyridines or purines. Further optimization of these two
fusion series led to compounds with subnanomolar potencies
against TrkA kinase in cellular assays. Antitumor effects in a
TrkA-driven mouse allograft model were demonstrated with
compounds 2d and 3a.
KEYWORDS: Trk, kinase inhibitors, imidazo[4,5-b]pyridines, purines, cancer
rk kinases belong to a subfamily of receptor tyrosine
through the aminopyrimidine, and modeling studies using a
homology model of TrkB suggested that the pyrazole binding
mode would be preferred. To confirm this prediction, we
T
kinases, which are important components in the cell
1
12
signaling cascade. Trks have three isoforms, TrkA, TrkB, and
TrkC, and all three isoforms are activated by the growth factor
determined the structure of the kinase domain of TrkA in
complex with 1a. TrkA adopts an inactive conformation with
the αC helix in a catalytically noncompetent orientation (and
the activation loop is not resolved in any of the three molecules
in the asymmetric unit). Compound 1a binds through the
pyrazole motif, forming hydrogen bonds to the backbone atoms
of Glu 590 and Met 592 (Figure 1). The isopropoxy group is
directed toward the gatekeeper Phe 589 side chain. The
fluoropyridine ring contacts the side chain of Leu 657, with the
fluorine atom in close proximity to the backbone carbonyl
atoms of Asn 665 and the Cα of Gly 667 N-terminal to the
DFG sequence of the activation loop. The pyrimidine N1 atom
does not make any direct contacts with TrkA protein side
chains, although it binds through water to Asp 596 NH and the
flexible side chains of Asp 596 and Arg 599 in a solvent-exposed
region of the ATP binding site. This heterocycle may therefore
serve primarily to place the pyrazole moiety and the
fluoropyridine groups appropriately.
2
ligands named neurotrophins. The binding of a neurotrophin
to the extracellular domain of Trk triggers the phosphorylation
of several key cytoplasmic tyrosine residues in the kinase
domain. These tyrosine residues in turn serve as the docking
sites for other downstream proteins and receptors and continue
3
the signal transduction pathways.
Early studies focused on the association of Trks with prostate
4,5
and pancreatic cancers.
However, in the past decade,
increasing evidence has suggested that Trk signaling has been
associated with a variety of other cancers, including neuro-
6
,7
blastoma, breast, and colon cancers. As a consequence, the
discovery of Trk kinase inhibitors has attracted considerable
8
−10
attention, and several classes have been disclosed.
While
available crystal structures for these receptors have been limited
to the extracellular domains, the crystal structure of the TrkC
kinase domain with a type II DFG-out oxindole inhibitor was
11
reported this year.
To further probe the SAR of this ring, other scaffolds were
then explored to replace the 2,4-disubstituted pyrimidine
moiety. It was found that Trk inhibitory potency was retained
for examples in which this ring was replaced with either phenyl,
We have previously reported compound 1a (AZ-23) that
showed potent TrkA/B inhibitory activities in vitro and in vivo
and possessed good physical and pharmacokinetic proper-
1
2,13
ties.
Treatment with 1a inhibited the growth of human
neuroblastoma xenograft tumors, and its combination with
topotecan resulted in the prolonged inhibition of tumor
regrowth. Theoretically, compound 1a could bind to the
Received: March 30, 2012
Accepted: July 26, 2012
Published: July 26, 2012
1
4
hinge region of the kinase either through the pyrazole or
©
2012 American Chemical Society
705
dx.doi.org/10.1021/ml300074j | ACS Med. Chem. Lett. 2012, 3, 705−709

ACS Medicinal Chemistry Letters
Letter
was reasoned that 3 would retain Trk potency since the
pyrazol-3-yl moiety was still present after the fusion. For 2, we
envisioned that the two nitrogen atoms on the pyrazole ring
would still make the key hydrogen bonds as before while the
third interaction might come from the weakly acidic C−H of
the imidazole ring. Binding modes from docking 2d and 3a to
the TrkA-1a receptor structure are illustrated in Figure 3.
Figure 1. Crystal structure of TrkA with 1a. TrkA is shown in a gray
stick representation, and 1a is shown in green. The weighted 2F − F
o
c
map is contoured at 1.5 σ (PDB: 4AOJ).
2
,6-disubstituted pyridyl, or the alternative 2,4-pyrimidine
8
regioisomer cores. In addition to monocyclic central ring
replacements, bicyclic ring systems were also examined. Fusions
of additional rings at the C-5 and the C-6 positions on the
pyrimidine ring (Figure 2) resulted in, for example, quinazo-
Figure 3. Proposed binding modes for 2d (top, cyan) and 3a (bottom,
orange) in the TrkA binding site as they overlay with 1a (green).
Hydrogen bonds are illustrated with dashed lines. The hydroxymethyl
substituents in each example form an additional hydrogen bond with
the backbone carbonyl oxygen of Glu 518 of the glycine-rich P loop.
Compounds 2a−e and 3a−c were synthesized from nitro-
substituted aromatic rings, a pyrazol-3-yl amine, and a
heteroaryl amine. For illustration purposes, syntheses of a
pair of imidazo[4,5-b]pyridines, compounds 2d and 3a, are
shown in Scheme 1. Preparation of 2d commenced from 3-
nitro-2,6-dichloropyridine 4. Reaction of 4 with a pyrazol-3-yl
amine 5a in the presence of triethylamine occurred
regioselectively to give the intermediate 6c in 30−60% yields.
A second nucleophilic aromatic substitution of intermediate 6c
with an amine 7a provided 8d in 50% yield. Reduction of the
Figure 2. Evolution of 5/6-bicyclic scaffolds.
line-2,4-diamino- and thieno[2,3-e]pyrimidine-2,4-diamino-
analogues that were indeed active, and their structure−activity
relationship (SAR) tracked those of the monocyclic pyrimidine
nitro group of 8d, either with H (atmospheric balloon) in the
2
1
5
core.
presence of palladium on activated charcoal or alternatively
Two other fusion options, however, are different from the
above in that one approach (Figure 2, path a) links the C-5
carbon (numbering based on 2,4-disubstituted pyrimidine
system) with the exocyclic amino group of the pyrazol-3-yl to
form a five-membered imidazole ring, while the second
approach (Figure 2, path b) links the central ring with the
nitrogen of the 1-heteroaryl ethanamino group to form another
with Zn/NH Cl followed by the cyclization using formamidine
4
acetate, resulted in the final compound 2d in 40−60% yield for
two steps. Compound 2e (an aminopyrazolylpurine analogue)
was synthesized in a similar fashion using 2,4-dichloro-5-nitro-
pyrimidine as the starting material. Following a similar
procedure to that described above for 2d, compound 3a was
constructed from 9 in a few steps in good yields. It should be
noted that in this case the nucleophilic aromatic substitution
with the amine 7a took place prior to the pyrazole substitution
with 5a.
5
-membered imidazole ring. The resulting two scaffolds belong
to the purine or imidazo[4,5-b]pyridine class, depending on the
number of nitrogen atoms included in the 6-membered ring. It
7
06
dx.doi.org/10.1021/ml300074j | ACS Med. Chem. Lett. 2012, 3, 705−709

ACS Medicinal Chemistry Letters
Letter
a
Scheme 1. Syntheses of Compounds 2d and 3a
a
Reagents and conditions: (a) CH CN, Et N, 30−60%. (b) BuOH, DIPEA, 40−50%. (c) Pd/C, H , MeOH. (d) Formamidine acetate, 40−60% for
3
3
2
two steps. (e) H SO , fuming HNO , 57%. (f) EtOH, 0 °C, 75%.
2
4
3
Table 1. Profiles of Compounds 2a−e and 3a−c
b
c
rat hep. Clint
rat iv Cl
human
T1/2 (h) F % sol (μM) PPB free (%)
a
a
a
d
compd
R1
Cp
R2
CH3
Y
cell (nM)
(μL/min/1E6)
(mL/min/kg)
hERG (μM)
2a
2b
2c
2d
2e
3a
3b
3c
N
0.24
281
48
NT
42
39
45
1.2
33
92
590
>1000
NT
16
39
6
>32
>32
>32
52
CH
CH3
CH3
N
0.82
0.97
2.3
3
i
O Pr
CH
CH
N
0.10
0.50
0.24
0.50
0.40
0.24
41
6.7
i
O Pr
CH OH
13
46
29
29
54
14
41
250
8.1
31
5.8
2
i
O Pr
CH3
24
130
51
3.8
480
>32
>25
32
i
O Pr
31
1.2
220
OEt
35
29
1.3
87
11
OCH3
29
33
3.2
150
15
>32
a
b
Assay conditions as in ref 12. For the cellular assay, all data are n = 1 except for 2b, which is the mean of two results. Assay details are in the
c
d
Supporting Information. Han Wistar rats, male. Ten mg/kg po (0.1% HPMC); 3 mg/kg iv (DMA/PEG/saline = 40/40/20). Assay conditions as
in ref 17.
Two series of compounds (2a−e and 3a−c) were profiled
cies, while a smaller group such as a methyl (2b) resulted in
significant loss of cellular potency. Both pyridine (2a, 2c, 2d,
and 3a−c) and pyrimidine (2e) central rings offered
for in vitro cell potencies, rat in vitro/in vivo pharmacokinetics
(
PK), physical properties, and hERG ion channel inhibitory
activities (Table 1). A constitutively active, TrkA-driven
2
comparable cellular potencies. At the R position, modeling
(
MCF10A-TrkA-Δ) cell-based mechanism of action (MOA)
suggested that an additional hydrogen bond could be made by
polar substituents (Figure 3, 2d); however, potency was not
improved as compared to 2c, likely due to competing
interactions with solvent. Regarding the pharmacokinetic
properties, these compounds have moderate to high clearances
assay was used as the primary cellular assay since most of these
compounds had reached the detection limit for the TrkA
enzyme assay (∼3 nM).
inhibition of cellular TrkA phosphorylation. Overall, these
compounds exhibited subnanomolar cellular potencies. The
SAR parallels that of monocyclic pyrimidine series. For
1
2,16
The end point of this assay is the
in rats when dosed intravenously. Intrinsic clearances (Cl ) of
int
these compounds in rat hepatocytes are also from moderate to
high. Compound 2d was profiled further in beagle dogs and
exhibited pharmacokinetic properties with a half-life of 1.0 h, a
clearance of 15.2 mL/min/kg, and an oral bioavailability of
1
example, a variety of R groups such as 2a (cyclopropyl), 2c
(
OiPr), 3b (OEt), and 3c (OCH ) were tolerated, and these
3
analogues had subnanomolar TrkA cellular inhibitory poten-
7
07
dx.doi.org/10.1021/ml300074j | ACS Med. Chem. Lett. 2012, 3, 705−709

ACS Medicinal Chemistry Letters
Letter
1
8
1
7%. The aqueous solubilities of these compounds are
generally greater than 100 μM, while the unbound fraction in
human plasma was measured in the range of 6−39%. The
17
hERG ion channel inhibitory activity of 1a (hERG IC : 5.2
50
μM) prompted us to evaluate the hERG activities of the fused
ring series, and all compounds in Table 1 exhibited greater than
2
5 μM IC50 against this channel.
One question was whether compounds in series 2 might have
a different selectivity profile than those in which the amino-
pyrazole binding motif was intact. In an in vitro enzyme panel
19
consisting of 82 kinases (Millipore), 2c was first screened at
0 μM, and any hits (defined as kinases where >30% inhibition
1
was seen) were followed up with dose−response curves.
Compound 2c was found to inhibit 18 kinases with IC values
50
less than 100 nM (Table 2). It had comparable potencies
Figure 4. Allograft efficacies of 2d and 3a.
Table 2. Kinase Selectivity Profile of 2c
kinase
Abl
enzyme IC50 (nM)
kinase
enzyme IC50 (nM)
1.2
1.4
2.1
2.2
3.5
5.5
6.1
8.7
13.4
FAK
17.2
18.2
30.6
34.1
44.3
64.0
68.3
72.2
99.8
In summary, we have described two novel series of inhibitors
against Trk kinases based on structure hopping from an earlier
Trk lead. Their proposed binding modes have been illustrated
through molecular docking to the first published crystal
structure of the TrkA kinase domain. Each of these two fusion
series could be either imidazo[4,5-b]pyridines or purines. These
compounds showed potent inhibition of TrkA in a cellular
assay. Assessment of the pharmacokinetic properties revealed
that these compounds had moderate to high clearance in
rodents and were orally bioavailable. In a TrkA-driven mouse
allograft tumor model, representative compounds from both
series demonstrated efficacy at doses as low as 1 mg/kg.
TrkA
FIt3
cSrc
TSSK2
ALK
Fgr
BTK
MLK1
FIt4
SIK
PhKy2
FGFR1
SAPK2a
JAK2
Itk
WNK3
against several kinases; however, given that 2c is 10-fold more
potent in the TrkA cellular assay, the limit of detection may
have been reached in the Millipore assay format. The
compound exhibits approximately 6-fold selectivity against
FGFR1. Compound 1a had been tested in an earlier version of
this assay panel (177 kinases) at 0.5 μM concentration; of
kinases inhibited by >75% in this screen, dose−response curves
for TrkA, TrkB, FGFR1, Flt3, Ret, MuSK, and Lck resulted in
IC50 values less than 100 nM. While it is challenging to
compare the data for 2c to the historical data for its matched
pair across differing panel, concentration, and selection criteria,
considering the metric of number of (non-Trk) kinases with
ASSOCIATED CONTENT
■
*
S
Supporting Information
Experimental procedures regarding TrkA protein purification
and crystallography, molecular docking, the rat hepatocyte
clearance assay, efficacy studies, synthetic procedures, and
analytical data for 2a−e and 3a−c. This material is available
free of charge via the Internet at http://pubs.acs.org.
13
IC less than 100 nM, it appears the chlorine atom at the hinge
50
AUTHOR INFORMATION
■
*
in 1a may confer additional selectivity over 2c. However, from a
cellular perspective, the effect of 1a on proliferation in
MCF10A-TrkA-Δ (1.51 nM) and MCF10A parental cells
Corresponding Author
E-mail: taowang2@gmail.com (T.W.) or michelle.lamb@
astrazeneca.com (M.L.L.).
(
2430 nM) was previously reported, with >1600-fold selectivity
13
resulting when signaling is driven through TrkA. In this assay,
c was more potent in both the TrkA-driven (0.05 nM) and the
Present Addresses
∥
2
Centaurus BioPharma Co., Ltd., Building #16, Yuquan
parental (192 nM) lines, with selectivity of >3800-fold.
Wisdom Vale, Minzhuang Road #3, Beijing 100195, China.
⊥
The in vivo antitumor effects of representative examples from
each series were examined in a 3T3-TrkA-Δ allograft mouse
model (Supporting Information). As illustrated in Figure 4,
both compounds demonstrated dose-dependent antitumor
activity in this model. At 1 mg/kg dose, both 2d and 3a
showed tumor growth inhibition (T/C: 12 and 30%,
respectively). Compound 2d exhibited tumor stasis (T/C:
Sirtris, A GSK Company, 200 Technology Square, Cambridge,
Massachusetts 02139, United States.
Peloton Therapeutics, Inc., 2330 Inwood Road, Suite 226,
Dallas, Texas 75235, United States.
Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado
#
∇
8
0301, United States.
Author Contributions
−
47%) at the 5 mg/kg dose, while regressions (T/C: −51 and
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript. The authors declare no competing financial
interest.
−
63%) were observed at both 5 and 25 mg/kg doses for 3a. A
significant tumor growth delay (approximately 4−5 days) was
seen with the 25 mg/kg dose of compound 3a. On average,
minimal body weight loss (less than 5%) was seen during the
dosing period in all treatment groups, including vehicle and
both compounds (data not shown).
Notes
The authors declare no competing financial interest.
7
08
dx.doi.org/10.1021/ml300074j | ACS Med. Chem. Lett. 2012, 3, 705−709

ACS Medicinal Chemistry Letters
Letter
(
15) Block, M. H.; Han, Y.; Josey, J. A.; Lee, J. W.; Scott, D.; Wang,
ACKNOWLEDGMENTS
■
B.; Wang, H.; Wang, T.; Yu, D. WO200549033, 2005.
16) Angeles, T. S.; Lippy, J. S.; Yang, S. X. Quantitative, High-
We thank Vladimir Capka for analytical support, Bob Young
and Bin Yang for helpful discussions, and Chungang Gu for the
hepatocyte assay. Kicki Blaho and Fredrik Lindqvist purified
̀
TrkA for crystallization, and Margareta Ek is acknowledged for
initial crystallization screening.
(
Throughput Cell-Based Assays for Inhibitors of TrkA Receptor. Anal.
Biochem. 2000, 278, 93−98.
(17) Bridgland-Taylor, M. H.; Hargreaves, A. C.; Easter, A.; Orme,
A.; Henthorn, D. C.; Ding, M.; Davis, A. M.; Small, B. G.; Heapy, C.
G.; Abi-Gerges, N.; Persson, F.; Jacobson, I.; Sullivan, M.; Albertson,
N.; Hammond, T. G.; Sullivan, E.; Valentin, J. P.; Pollard, C. E.
Optimisation and validation of a medium-throughput electrophysiol-
ogy-based hERG assay using IonWorks HT. J. Pharmacol. Toxicol.
Methods 2006, 54, 189−199.
REFERENCES
■
(
1) Gschwind, A.; Fischer, O. M.; Ullrich, A. The Discovery of
Receptor Tyrosine Kinases: Targets for Cancer Therapy. Nat. Rev.
Cancer 2004, 4, 361−370.
2) Patapoutian, A.; Reichardt, L. F. Trk Receptors: Mediators of
Neurotrophin Action. Curr. Opin. Neurobiol. 2001, 11, 272−280.
3) Pattarawarapan, M.; Burgess, K. Molecular Basis of Neuro-
trophin-Receptor Interactions. J. Med. Chem. 2003, 46, 5277−5291.
4) Sclabas, G. M.; Fujioka, S.; Schmidt, C.; Li, Z.; Frederick, W. A. I.;
(
18) Beagle dogs, male. Three mg/kg po (25% HP-β-cyclodextrin); 2
(
mg/kg iv (25% HP-β-cyclodextrin).
(19) http://www.millipore.com/drugdiscovery/dd3/KinaseProfiler.
(
(
Yang, W.; Yokoi, K.; Evans, D. B.; Abbruzzese, J. L.; Hess, K. R.;
Zhang, W.; Fidler, I. J.; Chiao, P. J. Overexpression of Tropomysin-
Related Kinase B in Metastatic Human Pancreatic Cancer Cells. Clin.
Cancer Res. 2005, 11, 440−449.
(
5) Weeraratna, A. T.; Arnold, J. T.; George, D. J.; DeMarzo, A.;
Isaacs, J. T. Rational Basis for Trk Inhibition Therapy for Prostate
Cancer. Prostate 2000, 45, 40−48.
(
6) Thiele, C. J.; Li, Z.; McKee, A. E. On TrkThe TrkB Signal
Tranduction Pathway Is an Increasingly Important Target in Cancer
Biology. Clin. Cancer Res. 2009, 15, 5962−5967.
(
7) Brodeur, G. M.; Minturn, J. E.; Ho, R.; Simpson, A. M.; Iyer, R.;
Varela, C. R.; Light, J. E.; Kolla, V.; Evans, A. E. Trk Receptor
Expression and Inhibition in Neuroblastomas. Clin. Cancer Res. 2009,
1
(
5, 3244−3250.
8) For a review, see Wang, T.; Yu, D.; Lamb, M. L. Trk Kinase
Inhibitors as New Treatments for Cancer and Pain. Expert Opin. Ther.
Pat. 2009, 19, 1−15.
(
9) Albanese, C.; Alzani, R.; Amboldi, N.; Avanzi, N.; Ballinari, D.;
Brasca, M. G.; Festuccia, C.; Fiorentini, F.; Locatelli, G.; Pastori, W.;
Patton, V.; Roletto, F.; Colotta, F.; Galvani, A.; Isacchi, A.; Moll, J.;
Pesenti, E.; Mercurio, C.; Ciomei, M. Dual Targeting of CDK and
Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-
8
48125, an Agent with Broad-Spectrum Antitumor Efficacy. Mol.
Cancer Ther. 2010, 9, 2243−2254.
10) Ghilardi, J. R.; Freeman, K. T.; Jimenez-Andrade, J. M.; Mantyh,
(
W. G.; Bloom, A. P.; Kuskowski, M. A.; Mantyh, P. W. Administration
of a Tropomyosin Receptor Kinase Inhibitor Attenuates Sarcoma-
induced Nerve Sprouting, Neuroma Formation and Bone Cancer Pain.
Mol. Pain 2010, 6, 87−97.
(
11) Albaugh, P.; Fan, Y.; Mi, Y.; Sun, F.; Adrian, F.; Li, N.; Jia, Y.;
Sarkisova, Y.; Kreusch, A.; Hood, T.; Lu, M.; Liu, G.; Huang, S.; Liu,
Z.; Loren, J; Tuntland, T.; Karanewsky, D. S.; Seidel, H. M.; Molteni,
V. Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in
Rodent Cancer Tumor Models. ACS Med. Chem. Lett. 2012, 3, 140−
145.
(
12) Wang, T.; Lamb, M. L.; Scott, D. A.; Wang, H.; Block, M. H.;
Lyne, P. D.; Lee, J. W.; Davies, A. M.; Zhang, H.-J..; Zhu, Y.; Gu, F.;
Han, Y.; Wang, B.; Mohr, P. J.; Kaus, R. J.; Josey, J. A.; Hoffmann, E.;
Thress, K.; MacIntyre, T.; Wang, H.; Omer, C. A.; Yu, D.
Identification of 4-Aminopyrazolylpyrimidines as Potent Inhibitors of
Trk Kinases. J. Med. Chem. 2008, 51, 4672−4684.
(
13) Thress, K.; MacIntyre, T.; Wang, H.; Whitston, D.; Liu, Z.-Y.;
Hoffmann, E.; Wang, T.; Brown, J. L.; Webster, K.; Omer, C.; Zage, P.
E.; Zeng, L.; Zweidler-McKay, P. A. Identification and Preclinical
Characterization of AZ-23, a Novel, Selective, and Orally Bioavailable
Inhibitor of the Trk Kinase Pathway. Mol. Cancer Ther. 2009, 8, 1818−
1827.
(
14) Zage, P. E.; Graham, T. C.; Zeng, L.; Fang, W.; Pien, C.; Thress,
K.; Omer, C.; Brown, J. L.; Zweidler-McKay, P. A. The Selective Trk
Inhibitor AZ623 Inhibits Brain-Derived Neurotrophic Factor-Medi-
ated Neuroblastoma Cell Proliferation and Signaling and is Synergistic
with Topotecan. Cancer 2011, 117, 1321−1329.
7
09
dx.doi.org/10.1021/ml300074j | ACS Med. Chem. Lett. 2012, 3, 705−709