Discovery of a potent, selective, and orally bioavailable c-met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl) -5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458)

Article abstract of DOI:10.1021/jm800401t

Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition of c-Met over VEGFR2. However, studies revealed the generation of active, n

Full text of DOI:10.1021/jm800401t

3688
J. Med. Chem. 2008, 51, 3688–3691
Table 1. c-Met and VEGFR2 Activities of Substituted Pyrazolones
Discovery of a Potent, Selective, and Orally
Bioavailable c-Met Inhibitor: 1-(2-Hydroxy-
2-methylpropyl)-N-(5-(7-methoxyquinolin-
4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-
2,3-dihydro-1H-pyrazole-4-carboxamide
(AMG 458)
Longbin Liu,*,† Aaron Siegmund,† Ning Xi,†
Paula Kaplan-Lefko,‡ Karen Rex,‡ April Chen,§
Jasmine Lin,§ Jodi Moriguchi,‡ Loren Berry,§ Liyue Huang,§
Yohannes Teffera,§ Yajing Yang,‡ Yihong Zhang,‡
Steven F. Bellon,| Matthew Lee, Roman Shimanovich,#
Annette Bak,# Celia Dominguez, Mark H. Norman,†
Jean-Christophe Harmange,[ Isabelle Dussault,‡ and
Tae-Seong Kim†
Amgen Inc., One Amgen Center DriVe,
Thousand Oaks, California 91320, Amgen Inc., One Kendall
Square, Building 1000, Cambridge, Massachusetts 02139, and
CHDI Management, Inc., 6080 Center DriVe, Suite 100,
Los Angeles, California 90045
ReceiVed April 7, 2008
Abstract: Deregulation of the receptor tyrosine kinase c-Met has been
implicated in human cancers. Pyrazolones with N-1 bearing a pendent
hydroxyalkyl side chain showed selective inhibition of c-Met over
VEGFR2. However, studies revealed the generation of active, nonselec-
tive metabolites. Blocking this metabolic hot spot led to the discovery
of 17 (AMG 458). When dosed orally, 17 significantly inhibited tumor
growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with
no adverse effect on body weight.
a Inhibitory constant for the kinase activities (substrate: gastrin). b IC50
(ip) value for HGF-mediated c-Met phosphorylation in PC3 cells. c IC50
(ip) value for VEGFR2-mediated survival of human umbilical vein
endothelial cells. See Table S1 for details.
models expressing activated c-Met.5 Herein, we describe the
discovery of a novel c-Met inhibitor that has on-target antitumor
activity in xenograft models and exhibits favorable pharmaco-
kinetic profiles in several animal species.6
c-Met is a receptor tyrosine kinase that is activated by its
ligand, hepatocyte growth factor/scatter factor (HGF/SF).1 Upon
activation, the intracellular C-terminal docking domain recruits
and subsequently activates a wide range of downstream signaling
molecules that contribute to the survival, proliferation, migration,
and invasion of cells.2 Transient activation of c-Met by HGF
through a paracrine mechanism is important during embryo-
genesis and tissue repair. However, overexpression of HGF and/
or c-Met or activating mutations of c-Met have been linked to
human cancers.
Among various approaches that target the c-Met/HGF signal-
ing pathway,3 inhibiting the c-Met kinase activity with small
molecules has the potential of blocking the ligand-dependent
and ligand-independent activation of c-Met. Most studies
involving c-Met inhibitors have been limited to in vitro
experiments because of the poor pharmacokinetic properties of
these agents.4 Recently, a dual c-Met/ALK (anaplastic lym-
phoma kinase) inhibitor exhibited antitumor effects in xenograft
During the course of searching for c-Met inhibitors, we
established that strong c-Met inhibition could be achieved with
pyrazolone 1 (Table 1).7 Compound 1 was also a potent inhibitor
of VEGFR2a with an affinity of 24 nM (Ki) and cellular potency
of 52 nM (IC50 in Huvec). VEGFR2 is involved in tumor
angiogensis that has been targeted with much success.8 To
specifically evaluate the effect of c-Met inhibiton on tumor
growth, we sought to improve the selectivity of 1 against
VEGFR2. Structural modifications revealed that replacing the
methyl group at the N-1 position by a propyl group (2)
significantly improved the selectivity, while branching of the
N-propyl group (3) resulted in lower activity. However,
introduction of a secondary hydroxyl group afforded similar
enzymatic and cellular activities to 2. In addition, good
selectivity over VEGFR2 was maintained for both enantiomers
(4, 5). Encouraged by these results, along with the fact that 2
was prone to P450-mediated hydroxylations at the N-propyl side
chain, we decided to evaluate these alcohols in vivo.
Both 4 and 5 were reasonably stable in human, rat, and mouse
liver microsomes (Clint: HLM < 55, RLM < 60, MLM < 45
(µL/min)/mg). In rat, they exhibited low clearance (CL < 200
(mL/h)/kg; t1/2 ) 1.9-2.6 h) and good oral bioavailability (F
> 50%). To assess the pharmacological activity of 4, inhibition
* To whom correspondence should be addressed. Phone: 805-447-3442.
Fax: 805-480-1337. E-mail: lliu@amgen.com.
†
Medicinal Chemistry, Amgen Inc., CA.
Oncology Research, Amgen Inc., CA.
Pharmacokinetics and Drug Metabolism, Amgen Inc., MA.
‡
§
|
Molecular Structure, Amgen Inc., MA.
Molecular Structure, Amgen Inc., CA.
Pharmaceutics, Amgen Inc., MA.
CHDI Management, Inc.
Medicinal Chemistry, Amgen Inc., MA.
#
a Abbreviations: VEGFR2, vascular endothelial growth factor receptor
2; AUC, area under the curve; HATU, 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-
tetramethyluronium hexafluorophosphate methanaminium.
[
10.1021/jm800401t CCC: $40.75
2008 American Chemical Society
Published on Web 06/14/2008

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3689
Scheme 1a
Figure 1. Concentration-time profiles of 4 and 6 in Balb/c mice
following oral administration of 4 (30 mg/kg).
of HGF-mediated c-Met phosphorylation in the mouse liver was
measured after oral administration. At 30 mg/kg, 4 inhibited
HGF-mediated c-Met phosphorylation by 98% at 6 h postdose.
However, detailed analysis of plasma samples from mice dosed
with 4 revealed the presence of significant amounts of ketone
6. As shown in Figure 1, 4 was rapidly converted to the
corresponding ketone, resulting in similar overall exposure for
the alcohol and the ketone [AUC(6)/AUC(4) ) 0.87]. These
findings immediately raised several concerns. (1) Ketone 6 is a
potent c-Met inhibitor (Ki ) 1.3 nM; IC50(PC3) ) 48 nM), and
it would likely exhibit c-Met inhibition in vivo. Therefore, the
presence of 6 would complicate the interpretation of the
pharmacodynamic (vide supra) and any efficacy studies with
4. (2) Ketone 6 is also a potent VEGFR2 inhibitor (Ki ) 2;
IC50(Huvec) ) 86 nM, Table 1). It is conceivable that this
antiangiogenic activity would contribute to the tumor growth
inhibition by 4 or 6 in future studies. For the purpose of
evaluating the effect of c-Met inhibitors on tumor growth, we
felt it would be desirable to test more selective compounds. (3)
When incubated in liver microsomes, the oxidation of 4 to 6
proceeded with different rates across species: while ketone 6
was the major metabolite in rat and mouse liver microsomes, it
was a minor metabolite in dog, monkey, and human liver
microsomes. Such cross-species variation in the formation of
an active metabolite such as 6 would render human dose
predictions, based on mouse efficacy studies of 4, difficult. The
stereoisomer 5 did not provide any advantage, as it showed a
metabolic profile similar to that of 4, indicating that the extent
of ketone formation was insensitive to the stereogenic nature
of the hydroxyl group.
a Conditions: (a) ClCO2Bn, Ca(OH)2, dioxane, 79%; (b) 1,1-dimethy-
loxirane, AlMe3, chlorobenzene, 42%; (c) H2, Pd/C (10%), MeOH, 98%;
(d) 2-fluoro-4-nitrophenol, chlorobenzene, 140 °C, 91%; (e) H2, Pd/C (10%),
EtOH, 57%; (f) 11, HATU, (iPr2)EtN, DMF, 60 °C, 68% (7), 70% (17);
(g) 6-bromopyridin-3-ol, chlorobenzene, 97%; (h) LiN(SiMe3)2, Pd2(dba)3,
2-(dicyclohexylphosphino)biphenyl, dioxane, 65 °C, 78%.
Despite the low cellular activity of the isopropyl derivative
3, the tertiary alcohol 7 inhibited c-Met phosphorylation in PC3
cells with an IC50 of 50 nM. Additionally, 7 was more selective
against VEGFR2 when compared to 4 or 5 (Table 1). In our
early SAR studies, we found that replacing the central fluo-
rophenyl ring with a pyridyl ring could be advantageous.7a Such
modification was expected to improve the physicochemical
properties (predicted change of log D at pH 6.5 is from 4.4 to
3.0) and mitigate the potential side effects associated with
quinone-imine formation.13 Therefore, in a similar manner,
quinoline 12 was converted to the biaryl ether 15. Amination
under Buchwald’s conditions14 led to 16, which was then
coupled with acid 11 to give 17 (Scheme 1). Compound 17
showed potent inhibition of c-Met at the enzyme and at the
cellular levels (Ki ) 1.2, IC50 ) 60 nM; Table 2). Furthermore,
it was active against several c-Met mutants that have been
identified in cancer patients.15 Compound 17 also showed greater
selectivity against VEGFR2 than 7. When tested against a panel
To circumvent the formation of ketone 6, we decided to
replace the secondary hydroxyl group in 4 or 5 with a tertiary
hydroxyl group.9 The synthesis of alcohol 7 is depicted in
Scheme 1. The installation of the requisite methylhydroxyethyl
group at the N-1 position of the pyrazolone was achieved using
the recently described selective alkylation of pyrazolone 9 with
oxiranes in the presence of Lewis acid catalysts.10 Commercially
available 5-methyl-2-phenyl-1,2-dihydropyrazol-3-one 8 was
converted to benzyl ester 9 according to the procedure of Lopez
et al.11 Treatment of 9 with excess 1,1-dimethyloxirane in the
presence of Me3Al led to the formation of alcohol 10 that was
converted to acid 11 in good overall yield. Concurrently,
7-methoxy-4-chloroquinoline 1212 was coupled with 2-fluoro-
4-nitrophenol and the resulting aryl ether 13 was hydrogenated
to give aniline 14. Finally, amide coupling between 11 and 14
in the presence of HATU afforded the desired tertiary alcohol
7 (Scheme 1).

3690 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Table 2. Enzyme and Cell Activities of 17
Letters
wild type and mutant enzymes (Ki, nM)a
cell (IC50, nM)
CT26c
human c-Met
1.2
mouse c-Met
2.0
V1092I
1.1
D1228H
2.2
M1250T
4.1
H1094R
0.5
Y1230H
4.5
VEGFR2
4100
PC3b
60
Huvecd
690
120
a Inhibitory constant for the kinase activities (substrate: gastrin, n > 2). b IC50 values for HGF-mediated c-Met phosphorylation in PC3 cells (human, n
> 4). c IC50 values for HGF-mediated c-Met phosphorylation in CT26 cells (mouse, n > 4). d IC50 value for VEGFR2-mediated survival of human umbilical
vein endothelial cells (n > 2).
Table 3. Preclinical Pharmacokinetic Properties of 17 in Animalsa
Balb/c mouse SD rat beagle dog cynomolgus monkey
CL ((L/h)/kg)
Vss (L/kg)
t1/2 (h)
0.16
0.31
1.3
0.73
0.62
1.0
0.34
0.75
2.8
0.10
0.56
5.7
F (%)
100
100
100
78
a iv dose: 1 mg/kg (20% Captisol with pH adjusted to 3.5 using
methanesulfonic acid). po dose: 10 mg/kg (2% HPMC and 1% Tween-80
with pH adjusted to 2.2 using HCl). Both were solution formulations with
the same drug concentration of 1 mg/mL.
of 55 tyrosine and serine/threonine kinases, 17 was >100-fold
selective over 98% and >1000-fold selective over 80% of the
panel.16
The in vitro potency and selectivity of the pyridyl derivative
17 warranted further evaluation of its pharmacokinetic proper-
ties. Compound 17 was metabolically stable in the liver
microsomes of mouse, rat, dog, monkey, and human with low
intrinsic clearances (Clint: <5, 62, 8, 8, 18 (µL/min)/mg,
respectively). The in vivo pharmacokinetic properties of 17 in
several animal species are summarized in Table 3. Compound
17 exhibited low clearances in mouse, dog, and monkey, and
low to moderate clearance in rat associated with low volume
of distribution at steady state that was less than or close to the
total body water of 0.6-0.8 L/kg in the animals tested. Although
17 was rapidly eliminated in mouse and rat with terminal half-
lives of less than 2 h, a more sustained exposure was achieved
in dog and monkey with half-life ranging from 3 to 6 h. When
administered orally, 17 achieved remarkably high bioavailability
in all species tested, in agreement with the observed in vitro
low metabolic turnover and high permeability.17
As a potent inhibitor of mouse c-Met (Ki ) 2.0, IC50(CT26)
) 120 nM; Table 2), 17 was evaluated in the mouse liver
pharmacodynamic assay. Oral dosing of 17 inhibited HGF-
mediated c-Met phosphorylation in a dose-dependent manner
with an approximate ED90 of 30 mg/kg and an associated plasma
exposure of approximately 15 µM at 6 h (Figure 2A). There
was a clear correlation between the inhibition of liver c-Met
phosphorylation and the plasma concentration of 17.
The antitumor effect of 17 as a single agent was then
examined in two xenograft models. It was first evaluated in the
NIH-3T3/TPR-Met model that was derived from NIH3T3 cells
transfected with human TPR-Met, a constitutively active, ligand-
independent, oncogenic form of c-Met (TPR-Met).18 In this
model, tumor growth is specifically driven by c-Met activation
that is independent of its ligand HGF/SF. When administered
orally q.d. or b.i.d., 17 induced dose-dependent tumor growth
inhibition with an ED50 of ∼12 mg/kg and an ED90 of ∼ 34
mg/kg (Figure 2B). Compound 17 was also evaluated in the
U-87 MG human glioblastoma xenograft model in which c-Met
is activated via its ligand HGF/SF through an autocrine loop.19
In this model, oral dosing of 17 inhibited tumor growth with
an ED50 of ∼16 mg/kg and an ED90 of ∼59 mg/kg (Figure 2C).
In both ligand-dependent and independent xenograft models,
17 significantly inhibited tumor growth at 30 and 100 mg/kg
q.d. and 30 mg/kg b.i.d. without adverse effect on body weight.
These encouraging results combined with favorable pharmaco-
Figure 2. Pharmocology and efficacy studies of 17 administered orally.
(A) Inhibition of HGF-mediated c-Met phosphorylation at 6 h in mouse
(Balb/c) liver. Terminal plasma concentration of 17 is indicated by the
black circles. (B) Tumor growth inhibition in the NIH-3T3/TPR-Met
xenograft model in nude mice. The AUC(0-24) at ED50 and ED90 were
96 and 241 µM·h, respectively. (C) Tumor growth inhibition in the
U-87 MG xenograft model in nude mice. The AUC(0-24) values at ED50
and ED90 were 130 and 482 µM·h, respectively. Arrow denotes the
first day of dosing.
kinetic profiles across species warranted advancement of 17 into
preclinical safety studies.
In conclusion, we identified N-(2-hydroxypropyl)pyrazolones
(4, 5) as selective c-Met inhibitors. However, the extensive in
vitro and in vivo conversion to significantly less selective ketone
6 posed a potential obstacle in evaluating the selective antitumor
effect of 4 and 5 as c-Met inhibitors. The ketone formation was
circumvented by replacing the oxidation-prone 2-hydroxypropyl

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3691
(6) For a preliminary discussion on the aspect of structural based design
leading to 17, see the following: Choquette, D.; Liu, L. ; Kim, T.-S.;
Norman, M. H.; Siegmund, A.; Xi, N.; Bellon, S. F.; Kaplan-Lefko,
P.; Lee, M.; Lin, J.; Rex, K.; Teffera, Y.; Dussault, I.; Harmange,
J. C. Discovery of AMG 458: An Orally Bioavailable, Selective c-Met
Inhibitor. Presented at the AACR Annual Meeting, San Diego, CA,
April 12-16, 2008.
group with a 2-hydroxy-2-methylpropyl chain. This led to
potent, selective, and stable c-Met inhibitors culminating in the
identification of 17 (AMG 458). The favorable profile of this
molecule justified its safety evaluation in preclinical species as
a potential clinical candidate for the treatment of human cancers.
(7) (a) The discovery and detailed SAR studies of 1 will be reported in a
separate publication. J. Med. Chem., to be submitted. (b) For the
synthesis and nomenclature of the pyrazolone piece leading to 4 and
5, see ref 10 (and ref 16 therein).
(8) (a) Baka, S.; Clamp, A. R.; Jayson, G. C. A review of the latest clinical
compounds to inhibit VEGF in pathological angiogenesis. Expert Opin.
Ther. Targets 2006, 10, 867–876. (b) Gasparini, G.; Longo, R.; Toi,
M.; Ferrara, N. Angiogenic inhibitors: a new therapeutic strategy in
oncology. Nat. Clin. Pract. Oncol. 2005, 2, 562–577.
Acknowledgment. We acknowledge Randall Hungate, Ter-
esa Burgess, Angela Coxon, Richard Kendall, and Robert
Radinsky for their guidance. We thank Daniel Retz and James
Rider for providing compounds 3 and 5, respectively.
Supporting Information Available: Analytical data and ex-
perimental protocols (PK, PD, xenograft, synthesis of 9-17). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(9) Other strategies to address the issue of ketone formation such as
protecting the OH group as methyl ether, or introducing alkyl groups
flanking the OH group, were less successful.
(10) Siegmund, A.; Retz, D.; Xi, N.; Dominguez, C.; Bu¨rli, R.; Liu, L.
Selective µ-hydroxyethylation at the N-1 position of a pyrazolone:
synthesis of benzyl 1-(µ-hydroxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazole-4-carboxylate. Synlett. 2008, 1005–1008.
(11) Lopez, R.; Leon, G.; Oliva, A. 4-Alkoxycarbonyl, 4-alkylthiocarbonyl
and 5-alkoxycarbonyloxy derivatives of 1-substituted-3-methylpyrazol-
5-ones. J. Heterocycl. Chem. 1995, 32, 1377–1379.
(12) Lauer, W. M.; Arnold, R. T.; Tiffany, B.; Tinker, J. Synthesis of some
chloromethoxyquinolines. J. Am. Chem. Soc. 1946, 68, 1268–1269.
(13) Nelson, S. D. Metabolic activation and drug toxicity. J. Med. Chem.
1982, 25, 753–765.
(14) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417–3419.
(15) Wang, W.; Marimuthu, A.; Tsai, J.; Kumar, A.; Krupka, H. I.; Zhang,
C.; Powell, B.; Suzuki, Y.; Nguyen, H.; Tabrizizad, M.; Luu, C.; West,
B. L. Structural characterization of autoinhibited c-Met kinase produced
by coexpression in bacteria with phosphatase. Proc. Natl. Acad. Sci.
U.S.A. 2006, 103, 3563–3568.
(16) The only other enzyme significantly inhibited by 17 is the c-Met related
protein RON (IC50 ) 8 nM). RON has also been implicated in human
cancers. (a) Danilkovitch-Miagkova, A.; Duh, F. M.; Kuzmin, I.;
Angeloni, D.; Liu, S. L.; Miller, A. D.; Lerman, M. I. Hyaluronidase-2
negatively regulates RON receptor tyrosine kinase and mediates
transformation of epithelial cells by jaagsiekte sheep retrovirus. Proc.
Natl. Acad. Sci. U.S.A. 2003, 100, 4580–4585. (b) Moderate activities
(<1000 nM) were found for the following kinases (IC50, nM): LCK
(730), FES (706), BLK (519), Lyn (506), FLT3 (391), BMX (363),
FGR (328), Aurora1(280), CFMS (238), CSK (165), PDGF (120),
ITK (62).
References
(1) (a) Bottaro, D. P.; Rubin, J. S.; Faletto, D. L.; Chan, A. M.; Kmiecik,
T. E.; Vande Woude, G. F.; Aaronson, S. A. Identification of the
hepatocyte growth factor receptor as the c-met proto-oncogene product.
Science 1991, 251, 802–804. (b) Naldini, L.; Weidner, K. M.; Vigna,
E.; Gaudino, G.; Bardelli, A.; Ponzetto, C.; Narsimhan, R. P.;
Hartmann, G.; Zarnegar, R.; Michalopoulos, G. K. Scatter factor and
hepatocyte growth factor are indistinguishable ligands for the MET
receptor. EMBO J. 1991, 10, 2867–2878.
(2) (a) Sattler, M.; Salgia, R. c-Met and hepatocyte growth factor: potential
as novel targets in cancer therapy. Curr. Oncol. Rep. 2007, 9, 102–
108. (b) Mazzone, M.; Comoglio, P. M. The Met pathway: master
switch and drug target in cancer progression. FASEB J. 2006, 20,
1611–1621. (c) Trusolino, L.; Comoglio, P. M. Scatter-factor and
semaphorin receptors: cell signaling for invasive growth. Nat. ReV.
Cancer 2002, 2, 289–300.
(3) (a) Jarvis, L. M. One pill, many uses. Chem. Eng. News 2007, 85,
15–23. (b) Christensen, J.; Burrows, J.; Salgia, R. c-Met as a target
for human cancer and characterization of inhibitors for therapeutic
intervention. Cancer Lett 2005, 225, 1–25. (c) Dussault, I.; Kaplan-
Lefko, P.; Jun, T.; Coxon, A.; Burgess, T. L. HGF- and c-Met-targeted
drugs: hopes, challenges and their future in cancer therapy. Drugs
Future 2006, 31, 819–825. (d) Abidoye, O.; Murukurthy, N.; Salgia,
R. Review of clinical trials: agents targeting c-Met. ReV. Recent Clin.
Trials 2007, 2, 143–147.
(4) (a) Sattler, M.; Pride, Y. B.; Ma, P.; Gramlich, J. L.; Chu, S. C.;
Quinnan, L. A.; Shirazian, S.; Liang, C.; Podar, K.; Christensen, J. G.;
Salgia, R. A novel small molecule met inhibitor induces apoptosis in
cells transformed by the oncogenic TPR-MET tyrosine kinase. Cancer
Res. 2003, 63, 5462–5469. (b) Christensen, J. G.; Schreck, R.;
Burrows., J.; Kuruganti, P.; Chan, E.; Le, P.; Chen, J.; Wang, X.;
Ruslim, L.; Blake, R.; Lipson, K. E.; Ramphal, J.; Do S Cui, J. J.;
Cherrington, J. M.; Mendel, D. B. A selective small molecule inhibitor
of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and
exhibits cytoreductive antitumor activity in vivo. Cancer Res. 2003,
63, 7345–7355.
(17) Compound 17 had an apparent permeability of 27 × 10-6 cm/s in
wild-type LLC-PK1 cells and good permeability in Caco-2 monolayer
in both directions (Papp(A-B): 32 × 10-6 cm/s; Papp(B-A)/Papp(A-
B): 0.8.
(18) Park, M.; Dean, M.; Cooper, C. S.; Schmidt, M.; O’Brien, S. J.; Blaire,
D. G.; Vande Woude, G. F. Mechanism of met oncogene activation.
Cell 1986, 45, 895–904.
(19) (a) Koochekpour, S.; Jeffers, M.; Rulong, S.; Taylor, G.; Klineberg,
E.; Hudson, E. A.; Resau, J. H.; Vande Woude, G. F. Met and
hepatocyte growth factor/scatter factor expression in human gliomas.
Cancer Res. 1997, 57, 5391–5398. (b) Huang, P. H.; Mukasa, A.;
Bonavia, R.; Flynn, R. A.; Brewer, Z. E.; Cavenee, W. K.; Furnari,
F. B.; White, F. M. Quantitative analysis of EGFRvIII cellular
signaling networks reveals a combinatorial therapeutic strategy for
glioblastoma. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 12867–12872.
(5) Zou, H. Y.; Li, Q.; Lee, J. H.; Arango, M. E.; McDonnell, S. R.;
Yamazaki, S.; Koudriakova, T. B.; Alton, G.; Cui, J. J.; Kung, P. P.;
Nambu, M. D.; Los, G.; Bender, S. L.; Mroczkowski, B.; Christensen,
J. G. An orally available small-molecule inhibitor of c-Met, PF-
2341066, exhibits cytoreductive antitumor efficacy through antipro-
liferative and antiangiogenic mechanisms. Cancer Res. 2007, 67, 4408–
4417.
JM800401T