Discovery and structural analysis of Eph receptor tyrosine kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.05.029

The Eph family of receptor tyrosine kinases has drawn growing attention due to their role in regulating diverse biological phenomena. However, pharmacological interrogation of Eph kinase function has been hampered by a lack of potent and selective Eph kin

Full text of DOI:10.1016/j.bmcl.2009.05.029

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4467–4470
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and structural analysis of Eph receptor tyrosine kinase inhibitors
Yongmun Choi a,b, , Farisa Syeda c,d, , John R. Walker d, , Patrick J. Finerty Jr. d, Dominic Cuerrier c,d
,
a,b,
Amy Wojciechowski a,b, Qingsong Liu a,b, Sirano Dhe-Paganon c,d, , Nathanael S. Gray
*
*
a Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney street, Boston, MA 02115, USA
b Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave, Boston, MA 02115, USA
c Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5G 1L5
d Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada M5G 1L5
a r t i c l e i n f o
a b s t r a c t
Article history:
The Eph family of receptor tyrosine kinases has drawn growing attention due to their role in regulating
diverse biological phenomena. However, pharmacological interrogation of Eph kinase function has been
hampered by a lack of potent and selective Eph kinase inhibitors. Here we report the discovery of com-
pounds 6 and 9 using a rationally designed kinase-directed library which potently inhibit Eph receptor
tyrosine kinases, particularly EphB2 with cellular EC50s of 40 nM. Crystallographic data of EphA3 and
EphA7 in complex with the inhibitors show that they bind to the ‘DFG-out’ inactive kinase conformation
and provide valuable information for structure-based design of second generation inhibitors.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 March 2009
Revised 6 May 2009
Accepted 8 May 2009
Available online 13 May 2009
Keywords:
Eph kinase
Ephrin
Type II kinase inhibitor
The Eph/ephrin family is the largest among tyrosine kinases and
is unique in that the ligands and receptors are both membrane
bound providing the possibility for bidirectional cell–cell signaling.
Genome analysis reveals that there are 14 Eph receptors and eight
ephrin ligands. Eph receptor signaling is responsible for arguably
the most diverse set of biological phenomena of any tyrosine ki-
nase family including organ development, tissue remodeling, neu-
ronal signaling, insulin secretion, and bone metabolism.1,2 Not
surprisingly, deregulation of ephrin-dependent signaling has been
implicated in pathological conditions related to all of these sys-
tems.3 The involvement of Eph/ephrin-signaling in tumorigenesis
has been the most extensively investigated due to frequent upreg-
ulation of Eph receptor or ligand expression in numerous tumor
types.4–6 The emerging picture is complicated by the diversity of
biological function that is associated with individual receptors
and ligands, including oncogenic or tumor suppressor functions.
The possibility of targeting Eph/ephrins therapeutically may be
the most straightforward in the context of inhibiting Eph/ephrin-
signaling in the vasculature as a means of preventing tumor angi-
ogenesis.2,6 Currently only a few small molecule Eph kinase inhib-
itors have been reported in the literature including 2,4-
diaminophenyl pyrimidines and 2,4-diaminophenyl triazines,7
and 3,7-diphenyl-4-amino-thieno and furo[3,2]pyridine8 EphB4
inhibitors.
To date the majority of investigation into functions of Eph
receptor tyrosine kinases has been accomplished using genetic
and biochemical methods. Pharmacological approaches, which
are crucial to understanding what happens upon acute inhibition
of Eph kinase activity, have been hampered by a lack of potent
and selective Eph kinase inhibitors. To address this deficiency we
undertook a survey of a collection of known kinase inhibitors for
their ability to target Eph kinase activity using an EphB2 kinase
activity-dependent cellular assay. Specifically we developed a cel-
lular assay where the murine pre-B cell line Ba/F3 was transformed
with DNA encoding a fusion protein between Tel and the kinase
domain of EphB2 such that the cells are capable of growing in
the absence of interleukin-3.9 EphB2 has been identified as a target
of dasatinib and nilotinib by proteomic10 and cellular screening9
approaches. As nilotinib is known to be a considerably more selec-
tive inhibitor than dasatinib, we decided to use nilotinib as a lead
compound and prepared a combinatorial library that should be
able to mimic the ‘DFG-out’ binding mode that nilotinib utilizes
to bind to Abl.11
Targeting of the kinase ‘DFG-out’ conformation is relatively
common; inhibitors of this class are termed type II inhibitors.12
An analysis of the structural features of these inhibitors reveals
that they conform to a pharmacophore model that consists of a
heterocyclic ‘head’ motif that recognizes the kinase hinge region,
a linker segment that traverses across the kinase ‘gatekeeper’ res-
idue and a ‘tail’ motif that occupies a hydrophobic pocket made
accessible by the flip of the ‘DFG-out’ motif.13 A solution-phase
* Corresponding authors. Tel.: +1 416 946 3876 (S.D.-P.); +1 617 582 8590
(N.S.G.).
E-mail addresses: sirano.dhepaganon@utoronto.ca (S. Dhe-Paganon), nathanael_
gray@dfci.harvard.edu (N.S. Gray).
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.05.029

4468
Y. Choi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4467–4470
combinatorial library of several hundred compounds was synthe-
sized where diverse heterocyclic ‘head’ motifs were attached to
three distinct linker-tail motifs (Fig. 1). The linker-tail motifs were
chosen to mimic functionality found in type II inhibitors such as
nilotinib,11 NVP-AST487,14 and sorafenib.15 Library synthesis con-
sisted simply of reacting an aniline from the linker-tail motif with
head groups using palladium mediated amination or amide-bond
forming chemistries. The compounds were purified by mass-trig-
gered reverse phase high pressure liquid chromatography and
characterized by mass and 1H NMR.
Using the Ba/F3 cellular assay, the library was screened in dose–
response format against a panel of 30 distinct tyrosine kinase
transformed Ba/F3 cells including Tel-EphB2.9 This screen revealed
that a subset of the library possessed inhibitory activity against
EphB2, c-Kit, Abl, Bcr-Abl, PDGFR, and FGFR2/3/4 (Supplementary
Table 1). Some compounds exhibited cross reactivity with Bcr-
Abl (inhibitors 1, 3, 7, 8) or FGFR2/3/4 (inhibitor 10). Abl, PDGFR,
and c-kit were the most frequently inhibited kinases by this com-
binatorial library which is consistent with these kinases being
known to be sensitive to type II inhibitors such as imatinib and nil-
otinib. The most potent and selective EphB2 inhibitors to emerge
from this initial library were inhibitors 6 (EC50 = 40 nM) and 9
(EC50 = 40 nM). Considerably less selective EphB2 inhibitors were
obtained such as 7 which also inhibits Ba/F3 cells transformed with
Tel fusions of EphA3, Kit, Fms, KDR, FLT1, FGR, Src, Lyn, Bmx, and
Bcr-Abl with EC50s below 500 nM.
and 9 exhibited a remarkably similar selectivity profile that con-
sisted of binding to a common set of kinases including b-raf, CSF1R,
DDR1, DDR2, EphA2, EphA5, EphA8, EphB1, EphB2, EphB3, Frk, Kit,
Lck, p38a, p38b, PDGFRa, PDGFRb, and Raf1. Inhibitor 7 inhibited
all these kinases and many more demonstrating how introduction
of the thiophene group can have a tremendous impact on kinase
selectivity. Inhibitors 6, 8 and 9 inhibited many members of the
Eph family with dissociation constants ranging from 96 nM to
520 nM; EphA6, A7 and B1 were not inhibited (Supplementary Ta-
ble 2). Kinase targets that were bound with dissociation constants
below 100 nM were tested in biochemical kinase activity assays
using the Invitrogen SelectScreenÒ Kinase Profiling Service (Life
Technologies Corporation, Madison, WI) to determine IC50 val-
ues.17 The compounds were assayed at a starting concentration
of 10
lM with threefold serial dilutions at [Km,app] ATP with the
exception of b-raf, which was conducted at 100
l
M ATP. The re-
sults demonstrate that compound 9 exhibits good selectivity for
Eph-family kinases with moderate potency but that there is vari-
able agreement between Kd and biochemical IC50 measurements
(Supplementary Table 3). These differences are not surprising as
the potency of inhibition by type II inhibitors has been demon-
strated to be highly dependent on the phosphorylation status of
the kinase, which differs between the binding and enzymatic ki-
nase assays.13 These compounds were also evaluated using a tem-
perature shift assay, which monitors the affinity-dependent
stability increase of proteins,18 to identify and rank-order ligands
that interact with Eph kinases, both in their untreated and fully-
auto-phosphorylated forms. We found that the auto-phosphoryla-
tion status of kinases did not significantly affect delta-Tm values
Compounds that inhibited Eph kinases (6–9) were further char-
acterized for specificity by screening against a panel of 402 kinases
that included a diverse array of serine/threonine and lipid kinases
as well as tyrosine kinases using the Ambit Biosciences Kinome-
Scan screening platform, which measures the relative binding of
the target molecule to each kinase.16 The compounds were tested
generated upon addition of ligands at 50 lM. Notably, EphA3, A5,
and B3 were stabilized more significantly by ligands than EphA7
(Supplementary Table 4), results consistent with the previous
assays.
at a single concentration of 10 lM (Supplementary Excel file I),
and compounds that resulted in greater than ninety percent dis-
placement relative to the DMSO control were subject to dose–re-
sponse determination of a dissociation constant. Inhibitors 6, 8
These results show that the Eph kinase family is also susceptible
to inhibition by type II compounds and suggest that our com-
pounds may also target the ‘DFG-out’ conformation. In order to
investigate the structural basis for how the inhibitors recognize
the Eph ATP-binding site we conducted extensive cocrystallization
trials of EphA3, A5, A7, and B3 with compounds 6–9. Two novel
complex structures were generated: a 1.8 Å co-crystal structure
of inhibitor 6 (ALW-II-38-3) with the EphA3 kinase domain
(Fig. 2a, PDB code 3dzq) as well as a 2.0 Å co-crystal structures of
inhibitor 9 (ALW-II-49-7) with the EphA7 kinase domain (Fig. 2b,
PDB code 3dko). The apo structure of EphA7 was also determined
to evaluate structural rearrangements; the apo EphA3 structure
has been reported previously.19 As expected based upon the design
strategy, both type II inhibitors induce the ‘DFG-out’ conformation
of the activation loop and preserve most of the inhibitor protein
interactions that have been observed in the nilotinib-Abl co-crystal
structure11 (Supplementary movie files highlighting the rearrange-
ment of the activation loops). Inhibitor 6 (ALW-II-38-3) forms four
direct hydrogen bonds to the ATP-binding cleft of EphA3: first be-
tween the inhibitor oxazole N and the backbone NH of the hinge
residue Met702, second between the oxazole amide NH and the
side chain hydroxyl of the gatekeeper Thr699, third between the
benzamide carbonyl oxygen and the backbone NH of Asp764 of
the ‘DFG-motif’ and fourth between the inhibitor benzamide NH
and the sidechain carboxylate of the catalytically essential
H
R
N
CF3
R2
N
H
O
R1
"Head"
R (Head)
"Tail"
R1
R2
H
No.
O
N
6
O
N
N
O
N
N
7
H
N
S
O
O
8
9
H
H
H
H
H
H
O
Glu670 located in the aC-helix. The inhibitor binding mode mimics
H2N
N
closely the bound conformation of nilotinib with Abl and an iden-
tical set of hydrogen bonds are formed. The 3-trifluoromethyl
group is a structural feature found in many type II inhibitors such
as nilotinib,11 INNO-406,20 sorafenib,15 and AST487.14 The contacts
formed by this group appear to be generally accessible in most co-
crystal structures of inhibitors with this structural feature suggest-
ing that it can contribute to potency but not selectivity.
N
N
10
N
H
N
Figure 1. Chemical structures of five representative library members are shown.

Y. Choi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4467–4470
4469
ATP-binding site. In the Abl-nilotinib co-structure the glycine loops
folds down and over the opening of the ATP-binding site with the
side chain of the loop’s tyrosine forming stacking interactions with
the inhibitor.11 In the EphA7-inhibitor 9 co-structure the glycine
rich loop, a portion of which is disordered, appears to stay above
the ATP-cleft in a much more commonly observed conformation.
In order to evaluate the ability of compound 9 to inhibit full
length endogenous EphB2 kinase activity, we used a glioblastoma
cell line (U87) which was reported to express EphB2 and showed
responsiveness to ephrinB1 ligand.22 The cells were either left un-
treated or treated with increasing concentrations of compound 9
for 1 h in the presence of ephrinB1. Immuoprecipitation of EphB2
followed by western blot analysis with an anti-phospho tyrosine
antibody revealed that compound 9 indeed inhibited ephrinB1-in-
duced autophosphorylation of EphB2 with an EC50 between
100 nM and 1 lM (Fig. 3). This result is in good agreement with
the data from the EphB2 kinase activity-dependent cellular assay.
We have discovered several type II inhibitors from a kinase-di-
rected combinatorial library with different selectivity profiles for
Eph receptor tyrosine kinases and other kinases. The most selective
inhibitors 6 and 9 inhibit cellular Tel-EphB2 Ba/F3 activity with
two digit nanomolar potency. These inhibitors can be considered
pan-Eph kinase inhibitors although they exhibit substantially re-
duced affinity for EphA1, A6, A7 and B1. The reduced activity
against EphA6 and A7 is presumably a result of these kinases not
possessing a threonine at the ‘gatekeeper position’. The structural
basis for reduced affinity towards EphA1 and B1 is not clear. Selec-
tivity profiling across a large panel of kinase binding assays re-
vealed that these compounds also exhibited significant affinity
for a subset of tyrosine kinases: CSF1R, Frk, Kit, Lck, DDR1, DDR2,
PDGFRa, PDGFRb and serine/threonine kinases: b-raf, p38a and
p38b (Supplementary Fig. 2). The cellular activities against Tel-
PDGFR and Tel-Kit have been validated using Ba/F3 assays. How-
ever, compounds 6 and 9 did not exhibit significant cellular activity
against Src-family kinases (using Tel-Src and Tel-Lyn) nor against
b-raf. Interestingly discrepancies between biochemical and cellular
assays for kinase inhibitors have been previously reported.23 Fur-
ther characterization of the potential cellular inhibitory activity
Figure 2. Complex Eph structures. (a) A slice of the active site of EphA3 in an
orientation optimal for showing all direct ligand interactions. Protein is in green
and compound 6 (ALW-II-38-3) in light orange with all nitrogen and oxygen atoms
colored blue and red, respectively. (b) The EphA7 and 9 (ALW-II-49-7) complex
structure is similarly shown, except protein is in purple and the ligand is colored
yellow. Secondary structures are shown in cartoon, protein residues in line, and
compounds in stick PyMol format. All potential hydrogen-bonding interactions,
with distances of less than four Angstroms, between ligand and protein are shown
as black, dashed lines.
of compounds 6 and 9 against CSF1R, Frk, DDR1, DDR2, p38a and
p38b will be required to validate whether the binding activity
translates into inhibition of cellular kinase activity. Screening of
structural analogs revealed that structural variations such as intro-
duction of a thiophene group (inhibitor 7) resulted in a dramatic
decrease in kinase selectivity.
The synthesis of novel type II inhibitors, which contain
hinge-interacting motifs with structures that extend into the
hydrophobic pocket adjacent to the ATP-site, has the potential to
deliver new inhibitors with unique kinase selectivity profiles. This
provides an efficient method of discovering new kinase inhibitors
that is complementary to high-throughput screening and medici-
Despite its relatively low affinity for EphA7, inhibitor 9 did
cocrystallize with the kinase domain binding to the DFG-out con-
formation. As with the apo EphA3, the apo EphA7 structure is in
the DFG-in conformation, where the side chain of Asp (764 in
EphA3 and 776 in EphA7) in the DFG motif points into the active
site, where it normally coordinates a Mg2+ ion. Inhibitor 9 makes
three hydrogen bonds to EphA7 that mimic those between inhibi-
tor 6 and EphA3: first between the pyridine N and the backbone
NH of the hinge residue Met714 and a second between the inhib-
itor benzamide carbonyl oxygen and the backbone NH of Asp776 of
the ‘DFG-motif’ and a third between the inhibitor benzamide NH
and the side chain carboxylate of Glu682. Inhibitor 9 is unable to
make a hydrogen bond to the gatekeeper residue because the gate-
keeper residue of EphA7 is an isoleucine and not a threonine as is
present in EphA3 and all other Eph kinases with the exception of
EphA6 (Supplementary Fig. 1). The consequence of this substitu-
tion is loss of a critical hydrogen bond between the inhibitor ani-
Ephrin B1 (2 µg/ml)
ALW II- 49 -7 (µM)
-
-
+
-
+
+
+
1
+
10
0.01 0.1
pY EphB2
EphB2
line NH and the sidechain hydroxyl of the Ile711 and
a
displacement of the methylphenyl moiety from its conformation
in the EphA3-crystal structure. Interestingly, an identical threonine
to isoleucine substitution of the gatekeeper position is also the
most recalcitrant of the Bcr-Abl mutations as it is not inhibited
by nilotinib.21 One major difference between EphA7 and Abl
structure is the glycine rich loop which forms the ‘roof’ of the
Figure 3. Compound 9 (ALW-II-49-7) inhibits EphB2 tyrosine kinase activity. The
U87 glioblastoma cells were either left untreated or treated for 1 h with indicated
concentrations of ALW-II-49-7 in the presence of ephrinB1. Total lysates were
subject to immunoprecipitation with an anti-EphB2 antibody, and immunoprecip-
itated EphB2 was analyzed by western blot with an anti-phosphotyrosine antibody
(top). The blot was reprobed with an anti-EphB2 antibody to show equal loading of
proteins (bottom).

4470
Y. Choi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4467–4470
5. Lugli, A.; Spichtin, H.; Maurer, R.; Mirlacher, M.; Kiefer, J.; Huusko, P.; Azorsa,
D.; Terracciano, L.; Sauter, G.; Kallioniemi, O. P.; Mousses, S.; Tornillo, L. Clin.
Cancer Res. 2005, 11, 6450.
6. Campbell, T. N.; Robbins, S. M. Curr. Issues Mol. Biol. 2008, 10, 61.
7. Bardelle, C.; Cross, D.; Davenport, S.; Kettle, J. G.; Ko, E. J.; Leach, A. G.; Mortlock,
A.; Read, J.; Roberts, N. J.; Robins, P.; Williams, E. J. Bioorg. Med. Chem. Lett. 2008,
18, 2776.
8. Miyazaki, Y.; Nakano, M.; Sato, H.; Truesdale, A. T.; Stuart, J. D.; Nartey, E. N.;
Hightower, K. E.; Kane-Carson, L. Bioorg. Med. Chem. Lett. 2007, 17, 250.
9. Melnick, J. S.; Janes, J.; Kim, S.; Chang, J. Y.; Sipes, D. G.; Gunderson, D.; Jarnes,
L.; Matzen, J. T.; Garcia, M. E.; Hood, T. L.; Beigi, R.; Xia, G.; Harig, R. A.;
Asatryan, H.; Yan, S. F.; Zhou, Y.; Gu, X. J.; Saadat, A.; Zhou, V.; King, F. J.; Shaw,
C. M.; Su, A. I.; Downs, R.; Gray, N. S.; Schultz, P. G.; Warmuth, M.; Caldwell, J. S.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 3153.
10. Rix, U.; Hantschel, O.; Durnberger, G.; Remsing Rix, L. L.; Planyavsky, M.;
Fernbach, N. V.; Kaupe, I.; Bennett, K. L.; Valent, P.; Colinge, J.; Kocher, T.;
Superti-Furga, G. Blood 2007, 110, 4055.
11. Weisberg, E.; Manley, P. W.; Breitenstein, W.; Bruggen, J.; Cowan-Jacob, S. W.;
Ray, A.; Huntly, B.; Fabbro, D.; Fendrich, G.; Hall-Meyers, E.; Kung, A. L.;
Mestan, J.; Daley, G. Q.; Callahan, L.; Catley, L.; Cavazza, C.; Azam, M.; Neuberg,
D.; Wright, R. D.; Gilliland, D. G.; Griffin, J. D. Cancer Cell 2005, 7, 129.
12. Liu, Y.; Gray, N. S. Nat. Chem. Biol. 2006, 2, 358.
13. Okram, B.; Nagle, A.; Adrian, F. J.; Lee, C.; Ren, P.; Wang, X.; Sim, T.; Xie, Y.;
Wang, X.; Xia, G.; Spraggon, G.; Warmuth, M.; Liu, Y.; Gray, N. S. Chem. Biol.
2006, 13, 779.
nal chemistry approaches. The scaffolds described here in conjunc-
tion with the crystallographic data should provide good starting
points for the design of inhibitors to specific Eph receptor tyrosine
kinases.
Acknowledgments
We thank Ambit Biosciences for performing KinomeScan profil-
ing, Invitrogen’s SelectScreenÒ Service for performing enzymatic
biochemical kinase activity profiling, Ivona Kozieradzki and her
team for providing cloning services for structural biology, and to
the Genomics Institute of the Novartis Research Foundation for
performing Ba/F3 cellular assays. Use of the Advanced Photon
Source at Argonne National Laboratory was supported by the U.
S. Department of Energy, Office of Science, Office of Basic Energy
Sciences, under Contract No. DE-AC02-06CH11357. This work
was funded by NIH grant GM079575-02. The Structural Genomics
Consortium is a registered charity (number 1097737) that receives
funds from the Canadian Institutes for Health Research, the Cana-
dian Foundation for Innovation, Genome Canada through the On-
tario Genomics Institute, GlaxoSmithKline, Karolinska Institutet,
the Knut and Alice Wallenberg Foundation, the Ontario Innovation
Trust, the Ontario Ministry for Research and Innovation, Merck &
Co., Inc., the Novartis Research Foundation, the Swedish Agency
for Innovation Systems, the Swedish Foundation for Strategic Re-
search and the Wellcome Trust.
14. Akeno-Stuart, N.; Croyle, M.; Knauf, J. A.; Malaguarnera, R.; Vitagliano, D.;
Santoro, M.; Stephan, C.; Grosios, K.; Wartmann, M.; Cozens, R.; Caravatti, G.;
Fabbro, D.; Lane, H. A.; Fagin, J. A. Cancer Res. 2007, 67, 6956.
15. Lyons, J. F.; Wilhelm, S.; Hibner, B.; Bollag, G. Endocr. Relat. Cancer 2001, 8, 219.
16. Karaman, M. W.; Herrgard, S.; Treiber, D. K.; Gallant, P.; Atteridge, C. E.;
Campbell, B. T.; Chan, K. W.; Ciceri, P.; Davis, M. I.; Edeen, P. T.; Faraoni, R.;
Floyd, M.; Hunt, J. P.; Lockhart, D. J.; Milanov, Z. V.; Morrison, M. J.; Pallares, G.;
Patel, H. K.; Pritchard, S.; Wodicka, L. M.; Zarrinkar, P. P. Nat. Biotechnol. 2008,
26, 127.
17. SelectScreenÒ customer protocol and assay conditions documents located at
www.invitrogen.com/kinaseprofiling.
18. Niesen, F. H.; Berglund, H.; Vedadi, M. Nat. Prot. 2007, 2, 2212.
19. Davis, T. L.; Walker, J. R.; Loppnau, P.; Butler-Cole, C.; Allali-Hassani, A.; Dhe-
Paganon, S. Structure 2008, 16, 873.
20. Kimura, S.; Naito, H.; Segawa, H.; Kuroda, J.; Yuasa, T.; Sato, K.; Yokota, A.;
Kamitsuji, Y.; Kawata, E.; Ashihara, E.; Nakaya, Y.; Naruoka, H.; Wakayama, T.;
Nasu, K.; Asaki, T.; Niwa, T.; Hirabayashi, K.; Maekawa, T. Blood 2005, 106,
3948.
21. Manley, P. W.; Cowan-Jacob, S. W.; Mestan, J. Biochim. Biophys. Acta 2005, 1754,
3.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.05.029.
References and notes
1. Arvanitis, D.; Davy, A. Gene Dev. 2008, 22, 416.
2. Pasquale, E. B. Cell 2008, 133, 38.
22. Nakada, M.; Niska, J. A.; Miyamori, H.; McDonough, W. S.; Wu, J.; Sato, H.;
Berens, M. E. Cancer Res. 2004, 64, 3179.
3. Merlos-Suarez, A.; Batlle, E. Curr. Opin. Cell Biol. 2008, 20, 194.
4. Mao, W.; Luis, E.; Ross, S.; Silva, J.; Tan, C.; Crowley, C.; Chui, C.; Franz, G.;
Senter, P.; Koeppen, H.; Polakis, P. Cancer Res. 2004, 64, 781.
23. Galkin, A. V.; Melnick, J. S.; Kim, S.; Hood, T. L.; Li, N.; Li, L.; Xia, G.; Steensma,
R.; Chopiuk, G.; Jiang, J.; Wan, Y.; Ding, P.; Liu, Y.; Sun, F.; Schultz, P. G.; Gray, N.
S.; Warmuth, M. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 270.