Discovery of orally active pyrrolopyridine- and aminopyridine-based Met kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.04.047

A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discover

Full text of DOI:10.1016/j.bmcl.2008.04.047

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 3224–3229
Discovery of orally active pyrrolopyridine- and aminopyridine-based
Met kinase inhibitors
Zhen-Wei Cai,* Donna Wei, Gretchen M. Schroeder, Lyndon A. M. Cornelius,
Kyoung Kim, Xiao-Tao Chen, Robert J. Schmidt, David K. Williams, John S. Tokarski,
Yongmi An, John S. Sack, Veeraswamy Manne, Amrita Kamath, Yueping Zhang,
Punit Marathe, John T. Hunt, Louis J. Lombardo,
Joseph Fargnoli and Robert M. Borzilleri
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA
Received 29 February 2008; revised 21 April 2008; accepted 22 April 2008
Available online 25 April 2008
Abstract—A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors
of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery
of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a
human gastric carcinoma xenograft model.
ꢀ 2008 Elsevier Ltd. All rights reserved.
Met is a receptor tyrosine kinase protein that has a high
binding affinity for hepatocyte growth factor/scatter fac-
tor (HGF/SF).1 Upon activation with its endogenous li-
gand HGF/SF, Met mediates various cellular responses,
such as epithelial cell dissociation (scattering), invasion,
tubular morphogenesis, and angiogenesis.2 While Met/
HGF signaling is essential for normal physiological
events, such as placental development and liver regener-
ation,3 aberrant activation of this pathway is reported to
lead to tumorigenicity and metastasis.4,5 Due to the
prevalence of Met amplification/overexpression and
mutations in a variety of human malignancies, inhibi-
tion of Met kinase activity by small molecules or biolo-
gics would likely have broad therapeutic utility.6 Several
reports have already indicated that inhibition of Met ki-
nase activity blocks tumor cell growth and invasion in
both in vitro and in vivo systems.7
opyridine 2 and aminopyridine 3 (Fig. 1). These chemo-
types also mimic the adenine group of ATP and allow
for the design of potent Met kinase inhibitors. In this re-
port, we describe the SAR optimization and in vivo
assessment of selected pyrrolopyridine- and aminopyri-
dine-based Met kinase inhibitors.
As shown in Table 1, two assays were used to evaluate
the activity of initial pyrrolopyridine and aminopyridine
analogs, 2 and 3, respectively. The Met kinase assay
measured the ability of a compound to inhibit enzymatic
activity of the Met receptor. The GTL-16 cellular assay
was used to assess the ability of the compounds to inhi-
bit the proliferation of this Met-driven (amplified Met)
human gastric carcinoma cell line. Both the malona-
mide-substituted pyrrolopyridine analog 2a and the
aminopyridine analog 3a demonstrated superior bio-
chemical potency compared to the pyrrolotriazine ana-
log 1a. The malonamide derivatives 2a and 3a
possessed potency comparable to the corresponding
acylurea analogs (2b and 3b) in the enzymatic assay;
however, they exhibited only moderate antiproliferative
activity in the cellular assay. The acylurea-substituted
pyrrolopyridine analog 2b displayed potent inhibition
of Met kinase activity with an IC50 value of 110 nM,
whereas the corresponding aminopyridine analog 3b
was three-fold more potent than 2b. In the GTL-16 cel-
lular proliferation assay, 2b provided nearly a two-fold
Recently, we disclosed a series of potent Met kinase
inhibitors with malonamide 1a and acylurea 1b groups
substituted on the pyrrolo[2,1-f][1,2,4]triazine scaffold
(Fig. 1).8 However, due to poor pharmacokinetic prop-
erties associated with compounds 1, we investigated
additional kinase inhibitor templates such as the pyrrol-
Keywords: Met; Receptor tyrosine kinase; Protein kinase inhibitors.
*
Corresponding author. E-mail: zhenwei.cai@bms.com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.04.047

Z.-W. Cai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3224–3229
3225
H
N
Introduction of substituents at the C3 position of pyr-
rolopyridine intermediate 89 was accomplished using
chemistry illustrated in Scheme 2. A Friedel-Crafts reac-
tion of 8 with bromoacetyl chloride in the presence of
AlCl3 afforded bromoacetyl ketone 9, which was treated
with the corresponding amines to provide the intermedi-
ates 10. Subsequent reduction of nitro group with zinc
powder and NH4Cl in MeOH, followed by treatment
with acylisocyanate 6, provided compounds 11a, b, c.
The synthesis of trichloromethyl ketone intermediate
12 was also carried out by a Friedel-Crafts reaction.
Compound 13 was prepared from 12 using a similar
reaction sequence for 11. Treatment of 13 with 3-amino-
methylpyridine in DMF gave the amide analog 14.
Reaction of 12 with NaOH in MeOH afforded the ester
intermediate 15. The ester analog 16 was obtained in a
similar manner as described for 11. Reduction of ester
16 with DIBAL in THF yielded the hydroxymethyl ana-
log 17.
F
F
O
O
O
R
R1
N
H
O
a
R =
N
R
R2
F
O
N
N
1
N
H
b
H
N
H
N
F
F
R
R3
O
O
R5
H2N
3
R4
2
N
N7
N
3
H
2
Figure 1. Met kinase inhibitors derived from different scaffolds.
Table 1. In vitro activities of compounds 1b, 2, and 3a
Compound
IC50 (lM)
The preparation of compound 20 is outlined in Scheme
3. The pyrrolopyridine intermediate 8 was protected
with a SEM group, and brominated with NBS in aceto-
nitrile to give intermediate 18. Palladium-catalyzed Su-
zuki coupling of bromo-intermediate 18 with aryl
boronic acid afforded the intermediate 19, which was
readily converted to compound 2013 in a three-step con-
secutive sequence involving reduction of nitro group
with Zn/NH4Cl in MeOH, followed by deprotection of
the SEM group with TBAF, and subsequent acylurea
formation with 6.
Kinase
GTL-16
1a (R1 = Me, R2 = H)
2a (R3 = R4 = H)
2b (R3 = R4 = H)
3a (R5 = H)
0.78
—
0.064
0.11
0.10
1.06
0.15
1.49
0.29
3b (R5 = H)
0.035
a For assay conditions, see Ref. 8.
increase in potency relative to 3b. Consistent with the
SAR observed in the series of pyrrolotriazine derivatives
1,8 the analogs with an acylurea moiety (2b and 3b) in
both the aminopyridine and pyrrolopyridine series pro-
vided 5- to 10-fold better cellular potency than those
corresponding analogs with malonamide substitution
(2a and 3a). Therefore, the SAR of only the acylurea-
substituted pyrrolopyridines and aminopyridines was
investigated further.
Incorporation of the pyridyl group at the C2 position of
pyrrolopyridine 24 was achieved by a Sonogashira reac-
tion11 of intermediate 2110 with 3-ethynylpyridine to
give 22. The intermediate 23 was obtained by reduction
of 22 with Zn/NH4Cl, and pyrrolopyridine formation in
the presence of KOtBu in NMP at elevated tempera-
ture.12 Acylurea formation was carried out in a similar
manner as depicted for 20, to provide desired analog 24.
The synthesis of compound 2a was accomplished by
standard amide bond coupling of aniline intermediate
49 and acid intermediate 5 as shown in Scheme 1. Treat-
ment of 4 with acylisocyanate 68 gave rise to 2b in mod-
erate yield. Aminopyridine analogs 3a and 3b were
obtained in a similar manner as 2a and 2b using the cor-
responding aniline 7.10
The chemistry to introduce substituents at the C3 posi-
tion of the aminopyridine core is outlined in Scheme
4.10 A Sonogashira reaction of 21 with various alkynes
gave rise to intermediates 25. The preparation of com-
pounds 26 was carried out using a similar reaction se-
quence as described for 16and followed by appropriate
functional group transformation as in the preparation
of 26e, g.
F
F
NH2
O
O
HO
N
O
H
The selected pyrrolopyridine analogs depicted in Table 2
were screened and optimized for Met kinase inhibitory
activity and anti-proliferation activity versus the GTL-
16 cell line. Various C3 and C2 substituents on the pyr-
rolopyridine core were well tolerated based on the enzy-
matic activity, and thus provided dramatically increased
potency relative to unsubstituted analog 2b. However,
the compounds in Table 2 displayed significant differ-
ences in cellular potency. The a-aminoacetyl substitu-
tions as in 11a, b, c were 2- to 10- fold more potent
than 2b in the enzyme assay, but they suffered from
more than 10-fold loss in inhibitory potency in the
GTL-16 proliferation assay, presumably due to poor cell
5
2a
a
N
H
N
4
F
NH2
N
C
O
b
O
N
O
3a, 3b
F
6
2b
H2N
7
Scheme 1. Reagents and conditions: (a) PyBOP, DIPEA, THF, rt, 75–
90%; (b) DCM, rt, 65–75%.

3226
Z.-W. Cai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3224–3229
H
O
N
O
F
NO2
F
NO2
b
F
NO2
R2
R1
N
F
NH
O
O
R2
Br
O
O
O
R1
N
O
a
c, d
F
O
N
N
N
H
N
N
N
10
H
H
N
H
N
8
9
H
H
11a, b, c
O
N
O
O
N
O
e
F
NH
F
NH
F
NO2
O
O
O
O
Cl
Cl
Cl
Cl
Cl
Cl
F
N
HN
O
O
F
f
c, d
N
N
N
H
N
H
N
H
N
14
12
13
H
H
O
N
O
O
N
O
g
F
NH
F
NH
F
NO2
O
O
F
O
O
F
O
O
HO
O
c, d
h
N
N
N
H
N
N
N
H
H
17
15
16
Scheme 2. Reagents and conditions: (a) 2-bromoacetyl chloride, AlCl3, DCE, rt, 78%; (b) R1R2NH, THF, rt, 65–90%; (c) Zn, NH4Cl, MeOH/THF,
rt, 70–95%; (d) 6, DCM, rt, 30–55%; (e) trichloroacetyl chloride, AlCl3, DCE, rt, 76%; (f) 3-aminomethylpyridine, DMF, rt, 61%; (g) 1 N NaOH,
MeOH, 61%; (h) DIBAL, THF, 0 ꢁC, 53%.
H
O
N
O
H2N
F
NO2
F
NH
N
a
F
NO2
c
F
NO2
S
O
O
F
O
Ar
Ar
Ar =
O
Br
d, e, f
a, b
N
N
SEM
N
N
N
N
SEM
N
H
N
H
N
b
20a,b
19
H
8
18
O
N
O
F
NH2
F
NH
F
NO2
d, h
F
NO2
g
N
O
O
N
F
O
O
f
N
N
I
N
H
N
N
H
H2N
N
H2N
N
21
24
23
22
Scheme 3. Reagents and conditions: (a) NaH, SEM-Cl, DMF, À40 to 0 ꢁC; (b) NBS, CH3CN, 0 ꢁC to rt, 92% for two steps; (c) aryl boronic acid,
Pd(PPh3)4, K3PO4, EtOH, toluene, 80 ꢁC, 75–82%; (d) Zn, NH4Cl, MeOH/THF, rt, 80–95%; (e) TBAF, THF, 50 ꢁC, 78–80%; (f) 6, DCM, rt, 30–
55%; (g) 3-ethynylpyridine, Pd(PPh3)4, CuI, Et3N, DMF, 85 ꢁC, 61%; (h) KOtBu, NMP, 80 ꢁC, 80%.
permeability. The pyridylmethyl amide analog 14 pre-
sents with similar potency to 11c in the enzymatic assay
with an IC50 value of 11 nM. The weakly basic pyridyl
amide analog 14 exhibited enhanced cellular potency
as compared to 11a–c. The methyl ester and hydroxy-
methyl analogs (16 and 17) demonstrated potent Met ki-
nase inhibition with IC50 values of 5 and 4 nM,
respectively. Compounds 16 and 17 also displayed good
cellular potency in the GTL-16 assay. Introduction of
heteroaryl groups directly at C3 (analogs 20a and 20b)
dramatically increased potency, especially in the GTL-
16 assay with in vitro IC50 values of 30 and 20 nM,
respectively. Inspired by the potency gained with the
C3 pyridyl-substituted analog 20b, the C2 pyridyl ana-
log 24 was also evaluated. Compound 24 demonstrated
comparable enzymatic and cellular potency to 20b.
Analysis of the X-ray co-crystal structures of com-
pounds 2b (Fig. 2) and 3b complexed with the Met ki-
nase domain, reveals that both inhibitors bind in a
similar fashion as pyrrolotriazine 1.8 These compounds
occupy the ATP binding site where the protein is in an
inactive conformation. The N7 nitrogen of pyrrolopyri-
dine 2b accepts a hydrogen bond from the hinge region
backbone NH of Met1160, while the pyrrole NH do-
nates a hydrogen bond to the carbonyl of Met1160.
The aminophenol ring and acylurea portion of both

Z.-W. Cai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3224–3229
Table 2. SAR of pyrrolopyridine seriesa
3227
H
O
N
O
F
NO2
H
N
O
O
F
NH
R6
O
R6
O
F
F
NH
b, c
a
21
F
O
R3
H2N
N
H2N
N
3
26a−c, e, f
25a−d, f
R4
2
26f: R6 = CH2NHBoc
g: R6 = CH2NH2
26a: R6 = CH2OH
b: R6 = CH2NMe2
c: R6 = 2-pyridyl
N
e
N
H
Compound R3
R4
H
IC50 (lM)
b, d, c
25d: R6 = TMS
26e: R6 = H
Kinase GTL-16
Scheme 4. Reagents and conditions: (a) R6–CCH, Pd(PPh3)4, CuI,
Et3N, DMF, 85 ꢁC, 50–80%; (b) Zn, NH4Cl, MeOH/THF, rt, 70–95%;
(c) 6, DCM, rt, 18–55%; (d) TBAF, THF, À30 to 0 ꢁC, 88%; (e) 35%
TFA in DCM, rt, 60%.
N
O
11a
0.044
0.019
1.05
1.47
HO
N
11b
11c
14
H
H
H
N
O
inhibitors bind similarly to previously discussed inhibi-
tors.8 The C3 position of the pyrrolopyridine ring points
toward the ribose pocket and the C2 position leads to
the surface-exposed extended hinge region. Before inter-
acting with the mixed-polarity solvent-accessible area of
the protein, the C2 and C3 substituents must first bypass
the steric demand of the mostly hydrophobic pinched-in
area of the protein, that is, the bite between the P-loop
and extended hinge region comprised of residues such
as Ile1084 and Gly1163. Analogs in Table 2 likely satisfy
this requirement and thus, have the opportunity to in-
crease interactions with the protein surface. Specifically,
the pyridyl analogs 20b and 24 optimize the interactions
with protein in the solvent-accessible pockets and pro-
vide dramatic improvement in kinase inhibitory activity.
These two compounds were evaluated further in phar-
macokinetic studies.
0.011
0.011
2.22
0.65
N
O
N
O
HN
O
16
17
H
H
0.005
0.004
0.18
0.18
O
HO
NH2
N
The aminopyridine core of 3b engages in similar interac-
tions as 2b with the hinge region (Fig. 2), namely, the
backbone NH of Met1160 donates a hydrogen bond
to the pyridine N1 and the backbone carbonyl of
Met1160 accepts a hydrogen binding from the 2-amino
group. The C3 position of the aminopyridine points to
the ribose/extended hinge region. The SAR at the C3 po-
sition of aminopyridine core was explored by using an
alkyne as a spacer to extend groups toward the protein
surface. The potential increase in binding affinity was
realized, as demonstrated in the improved biochemical
activities achieved with aminopyridine analogs 26 (Table
3). The propargyl analog 26a and the unsubstituted ana-
log 26e displayed IC50 values of low single digit nM in
biochemical assay, and IC50 values of 30 and 40 nM in
the cellular assays, respectively. The basic groups such
as Me2N in 20b and NH2 in 20g provided potent enzy-
matic activity; however, only moderate cellular activity
was observed. Installation of the weakly basic pyridyl
group gave the analog 26c with improved potency in
Met kinase and cellular assays. The analogs were subse-
quently screened for inhibitory activity against an in-
house panel of human CYP P450 isozymes. The analogs
26a, b, e, g containing small substituents on the alkyne
moiety demonstrated significant inhibition of CYP3A4,
whereas 26c showed only weak activity against CYP3A4
20a
H
0.007
0.03
S
N
20b
24
H
0.002
0.002
0.02
0.03
N
H
a For assay conditions, see Ref. 8.
isozyme. Thus, compound 26c was chosen for further
characterization.
As shown in Table 4, five compounds with potent inhib-
itory activity in the GTL-16 assay were screened for in
vitro metabolic stability using human (HLM) and
mouse (MLM) liver microsome systems.14 Low meta-
bolic rates were observed for all five compounds. There-
fore, they were subsequently evaluated in preliminary
pharmacokinetic studies in mice (Table 4). Following
oral administration of a 50 mg/kg dose, compounds 2b
and 24 demonstrated low plasma levels of drug, whereas
3b, 20b, and 26c yielded moderate to high exposures.

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Z.-W. Cai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3224–3229
Table 4. Metabolic stability and mouse exposure data following oral
administration of selected compoundsa
Compound HLM/MLMa
rate nmol/
min/mg
Mouse oral exposureb,c
Tmax AUC (lM h)
(0–4 h) (0–8 h)
Cmax
(lM)a (h)
2b
3b
0.015/0.035
0.000/0.018
0.038/0.049
0.016/0.036
0.000/0.042
2.4
10.5
6.0
4.0
4.0
4.0
4.0
4.0
6.0
33.0
—
—
—
20b
24
34.0
11.4
85.0
2.1
16.0
—
—
26c
a Compounds at 3 lM incubated in 10 mg of protein (HLM or MLM)
for 10 min.
b Dosed at 50 mg/kg, all values are means of at least three mice.
c Vehicle: PEG400/water (1:1).
Table 5. Antitumor activities of compounds 20b, 3b, and 26c in the
GTL-16 xenograft model in micea
Figure 2. A close-up of the X-ray co-crystal structure of 2b (in green)
and 3b (in magenta) in the Met ATP binding site (only the protein
bound with 2b is shown). The binding region of the protein is rendered
in a surface representation and colored by the associated atoms of the
protein (carbon: white, oxygen: red, nitrogen: blue, and sulfur:
orange). PDB code: 3CTJ for 2b and 3CTH for 3b.
Compound
3b
20b
26c
Dose (mg/kg)
%TGI
25
<50
75
80
125
98
50
67
100
88
50
<50
a Vehicle: PEG400/water (1:1).
vided good antitumor activity (%TGI = 80) at the
75 mg/kg dose level and complete tumor stasis
(%TGI = 98) at the 125 mg/kg dose level. Compound
26c exhibited no antitumor activity at the 50 mg/kg dose
level, which may be attributed to its high plasma protein
binding in mouse (99.98%). Compound 20b displayed
antitumor activity when administered at doses of 50
and 100 mg/kg with %TGI values of 67% and 88%,
respectively. Figure 3 represents the dose-dependent tu-
mor growth inhibition of 20b in GTL-16 model. The
50 mg/kg dose level provided tumor growth delay as
compared to the vehicle treated control group, while
nearly complete tumor stasis was achieved during the
dosing regimen at the 100 mg/kg dose level.
Table 3. SAR of aminopyridine seriesa
H
O
O
N
F
NH
R6
F
O
H2N
N
Compound
R6
IC50 (lM)
Kinase
0.003
GTL-16
CYP3A4
0.7
HO
26a
26b
0.03
0.22
In conclusion, pyrrolopyridine- and aminopyridine-
based acylurea analogs proved to be potent inhibitors
of Met kinase activity. Compounds 3b and 20b demon-
N
0.004
0.005
2.7
26c
0.04
37.0
1000
N
26e
26g
H
0.002
0.005
0.04
0.25
0.8
1.8
Control 50% PEG400
+ 50% H2O
750
500
250
0
H2N
50 mg/kg
a For assay conditions, see Ref. 8.
100 mg/kg
Based on the high systemic exposures, compounds 3b,
20b, and 26c were further evaluated in an in vivo efficacy
study using GTL-16 xenografts implanted in athymic
mice.14 These compounds were administered orally at
various dose levels once daily for 14 days, and their per-
cent tumor growth inhibition data (%TGI)15 are shown
in Table 5. Compound 3b did not demonstrate antitu-
mor activity at a low dose of 25 mg/kg; however, it pro-
12
22
32
Days post-implant
Figure 3. Antitumor activity of 20b against GTL-16 xenografts
implanted in the athymic mice. Arrows indicate dosing.

Z.-W. Cai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3224–3229
3229
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Holt, R. U.; Ro, T. B.; Fagerli, U.-M.; Hjorth-Hansen,
8. Schroeder, G. M.; Chen, X.-T.; Williams, D. K.; Nirschl,
D.; Cai, Z.-W.; Wei, D.; Tokarski, J. S.; An, Y.; Sack, J.;
Chen, Z.; Huynh, T.; Vaccaro, W.; Poss, M.; Wautlet, B.;
Gullo-Brown, J.; Kellar, K.; Manne, V.; Hunt, J. T.;
Wong, T. W.; Lombardo, L. J.; Fargnoli, J.; Borzilleri, R.
M. Bioorg. Med. Chem. Lett. 2007, 18, 1945.
9. Borzilleri, R. M.; Chen, Z.; Huynh, T. N.; Vaccaro, W.;
Chen, X.-T.; Kim, K. S. PCT Int. Patent Appl. WO 2006/
004636, 2006.
10. Borzilleri, R. M.; Cornelius, L. A. M.; Schmidt, R. J.;
Schroeder, G. M.; Kim, K. S. U.S. Patent Appl. 2005/
0245530, 2005.
11. Feuerstein, M.; Berthiol, F.; Doucet, H.; Santelli, M.
Synthesis 2004, 1281.
12. Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P.
Angew. Chem. Int. Ed. 2000, 39, 2488.
13. Representative analytical data for 20b: HPLC
Rt = 2.80 min, purity = 98% (Conditions: Phenomenex
5 lm 4.6· 50 mm column, 4 min gradient from 10% to
90% aqueous MeOH with 0.1% TFA, wavelength detected
at 220 nM); 1H NMR (500 MHz, DMSO-d6) d 12.71 (br s,
1H), 11.04 (br s, 1H), 10.61 (br s, 1H), 9.17 (s, 1H), 8.84 (d,
1H, J = 8.25 Hz), 8.74 (d, 1H, J = 5.50 Hz), 8.20 (d, 1H,
J = 5.50 Hz), 8.11 (s, 1H), 8.06 (dd, 1H, J = 8.25, 5.50 Hz),
7.78 (dd, 1H, J = 12.65, 2.20 Hz), 7.50–7.30 (m, 4H), 7.20–
7.10 (m, 2H), 6.41 (d, 1H, J = 6.05 Hz), 3.75 (s, 2H); LC–
MS (ESI+) m/z 500 (M+H)+; 3b: HPLC Rt = 1.94 min,
1
purity = 98%; H NMR (400 MHz, DMSO-d6) d 13.43 (s,
1H), 11.09 (s, 1H), 10.65 (s, 1H), 8.00–7.90 (m, 1H), 7.87–
7.83 (m, 2H), 7.48–7.45 (m, 2H), 7.43–7.38 (m, 2H), 7.21–
7.15 (m, 2H), 6.71 (dd, 1H, J = 7.23, 2.50 Hz), 6.16 (d, 1H,
J = 2.38 Hz), 3.77 (s, 2H); LC–MS (ESI+) m/z 389
(M+H)+; HRMS (M+H)+: found: 399.1258, calcd:
399.1269.
14. For experimental details see: Borzilleri, R. M.; Zheng, X.;
Qian, L.; Ellis, C.; Cai, Z.-W.; Wautlet, B. S.; Mortillo, S.;
Jeyaseelan, R.; Kukral, D. W.; Fura, A.; Kamath, A.;
Vyas, V.; Tokarski, J. S.; Barrish, J. C.; Hunt, J. T.;
Lombardo, L. J.; Fargnoli, J.; Bhide, R. S. J. Med. Chem.
2005, 48, 3991.
15. For a detailed definition for %TGI, see Ref. 14. Antitumor
activity of drug is defined as a %TGI > 50%.