Design, synthesis, and biological activity of 4-(imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-phenylbenzamide derivatives as BCR–ABL kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.10.007

A series of 4-((pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)phenyl-3-benzamide derivatives and 4-((imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-)phenyl-3-benzamide derivatives were designed, synthesized as new BCR–ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. These new compounds were screened for BCR–ABL1 kinase inhibitory activity, and most of them appeared good inhibitory activity against BCR–ABL1 kinase. One of the most potent compounds 16a strongly suppressed BCR–ABL1 kinase with IC₅₀value of 8.5 nM. The tested compounds 16a and 16i showed strong inhibitory activities against K562 with IC₅₀value of less than 2 nM. Molecular docking studies indicated that these compounds fitted well with the active site of BCR–ABL1 protein. The results showed these inhibitors may serve as lead compounds for further developing new drugs targeted BCR–ABL kinase.

Full text of DOI:10.1016/j.bmcl.2016.10.007

Accepted Manuscript
Design, synthesis, and biological activity of 4-(imidazo[1,2-b]pyridazin-3-
yl)-1H-pyrazol-1-yl-phenylbenzamide derivatives as BCR-ABL kinase inhibi-
tors
Liming Hu, Tingting Cao, Yongjuan Lv, Yiming Ding, Leifu Yang, Qiang
Zhang, Mingzhou Guo
PII:
S0960-894X(16)31035-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.10.007
BMCL 24310
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
1 May 2016
1 October 2016
5 October 2016
Please cite this article as: Hu, L., Cao, T., Lv, Y., Ding, Y., Yang, L., Zhang, Q., Guo, M., Design, synthesis, and
biological activity of 4-(imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-phenylbenzamide derivatives as BCR-
ABL kinase inhibitors, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.
2
016.10.007
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Design, synthesis, and biological activity of 4-
(
imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-
yl-phenylbenzamide derivatives as BCR-
ABL kinase inhibitors
a
a
a
a
b
b
Liming Hu , Tingting Cao , Yongjuan Lv , Yiming Ding , Leifu Yang , Qiang Zhang , Mingzhou
c
Guo

Bioorganic & Medicinal Chemistry Letters
Design, synthesis, and biological activity of 4-(imidazo[1,2-b]pyridazin-3-yl)-1H-
pyrazol-1-yl-phenylbenzamide derivatives as BCR-ABL kinase inhibitors
a
a
a
a
b
b
c
Liming Hu , Tingting Cao , Yongjuan Lv , Yiming Ding , Leifu Yang , Qiang Zhang , Mingzhou Guo
a
College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China
Beijing Scitech-MQ pharmaceuticals Limited, Beijing 101320, China
Chinese PLA General Hospital, Beijing 100853,China
b
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of 4-(pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)phenyl-3-benzamide derivatives
and 4-(imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives were
designed, synthesized as new BCR-ABL tyrosine kinase inhibitors by using combinational
strategies of scaffold hopping and conformational constraint. These new compounds were
screened for BCR-ABL1 kinase inhibitory activity, and most of them appeared good inhibitory
activity against BCR-ABL1 kinase. One of the most potent compounds 16a strongly suppressed
BCR-ABL1 kinase with IC50 value of 8.5 nM. The tested compounds 16a and 16i showed strong
inhibitory activities against K562 with IC50 value of less than 2nM. Molecular docking studies
indicated that these compounds fitted well with the active site of BCR-ABL1 protein. The
results showed these inhibitors may serve as lead copounds for further developing new drugs
targeted BCR-ABL kinase.
Keywords:
BCR-ABL inhibitors
Bioactivity
Molecular docking
Chronic myeloid leukaemia
Protein kinases are involved in multiple signaling pathways in
the cellular processes including growth, survival, invasion and
angiogenesis during tumour initiation and progression. ABL
the identification of the disease mechanism, imatinib, the first
approved tyrosine kinase inhibitor, was developed and used to
treat CML targeting the inhibition of BCR-ABL kinase (Fig. 1).
1
9
tyrosine kinase inhibitors, the most successful TKIs, have been
used for the treatment of chronic myeloid leukaemia (CML)
which is a haematological cancer caused by the Philadelphia pos-
itive(Ph+) human leukaemias as a consequence of the t(9;22)
As a first-generation Bcr-Abl kinase inhibitor, imatinib has
achieved great clinical success and became the first-line drug for
the treatment of CML. However, multiple drug resistance of tu-
mor cells against the existing BCR-ABL TKIs has emerged due
2
-4
10
(q34;q11) chromosome translocation. The ABL kinase which is
to the mutations in the ABL kinase domain or other reasons.
T315I
a proto-oncogene protein tyrosine kinase involved in cell differ-
entiation, migration and signaling suffers an oncogenic activation
in Ph+ human leukaemias where generating a breakpoint cluster
region–Abelson (BCR-ABL) fusion protein with constitutive
BCR-ABL
is the most common mutation which occurs from
the replacement of the so-called “gatekeeper” threonine residue
at position 315 with isoleucine, where it sacrifices a favourable
hydrogen bonding interaction between imatinib and Thr 315 and
imposes an unfavourable steric clash due to the bulky isoleucine
5
tyrosine kinase activity. According to BCR-ABL fusion
11
oncoprotein, several mechanisms are involved in the malignant
side chain. The emergence of resistance leads to the develop-
ment of a second generation of BCR-ABL tyrosine kinase inhibi-
6
transformation. First, the speed of cell division is accelerated
12-14
because of the activations of some cell cycle controlling enzymes
and proteins caused by BCR-ABL. Subsequently, mitogenic sig-
naling pathways are constitutively activated by the BCR-ABL
fusion oncoprotein such as the janus kinase (JAK)/signal trans-
tors such as nilotinib, dasatinib, and bosutinib.
These TKIs
have been approved as second-line drugs to treat adult patients in
all phases of CML with resistance to imatinib. Many other inhibi-
tors, such as bafetinib, have also been developed in late-stage
15
duction
and
transcription
(STAT)
pathway,
clinical trials (Figure 1). Although these BCR-ABL inhibitors
have been synthesized or approved to be second-line drugs, drug
resistance remains an unmet clinical challenge for CML treat-
phosphaditylinositide-3 (PI3) kinase pathway, RAS/mitogen-
activated protein kinase (MAPK) pathways, and the myc path-
7
16
way.
ment.
Since the BCR–ABL protein exists in greater than 90% of
Asp381-Phe382-Gly383, known as the “DFG-motif” (derived
from the single letter amino acid code) was three highly con-
served amino acid residues in the binding region between the
CML cases, it has become a well-validated and novel target for
8
designing small molecular inhibitors to treat CML. Following
—
——

Corresponding author. Tel.: +86 10 6739 6211.
e-mail: huliming@bjut.edu.cn

core of these BCR-ABL kinase inhibitors and the ATP-binding
region. These inhibitors can be divided into two types depending
BCR-ABL kinase showed that most of the compounds possessed
four key structural elements which formed crucial interactions
with the protein: (1) “head region”, a heterocyclic moiety inter-
acting via hydrogen bond with the hinge region; (2) “middle
part”, a methylphenyl group occupying the back cavity influ-
enced by gatekeeper residue; (3) “tail region”, an additional hy-
drophobic group bringing hydrophobic interactions within the
allosteric site induced by the DFG-out conformation; (4) “linker
part”, a suitable linker between the head region and the middle
2,17
on their modes of binding. The bindings between Type 1 ki-
nase inhibitors and the “DFG-in” conformation as the active form
of the kinase are similar to ATP-binding. So the inhibitors can
prevent phosphorylation through competitive inhibition of the
ATP-binding site. By contrast, the bindings between Type 2 in-
hibitors and a hydrophobic pocket adopting the inactive “DFG-
out” conformation are directly adjacent to the ATP-binding site.
As a result, the kinase is locked in a conformation that it is una-
ble to bind ATP and preventing catalysis. Inhibitor selectivity is
therefore achieved by binding to regions where the structure is
less conserved in the inactive form of the kinase. Imatinib
demonstrates the selectivity achieved by a Type 2 inhibitor, so
does some second generation of BCR-ABL tyrosine kinase inhib-
itors such as nilotinib, bafetinib. Recently, the third-generation
BCR-ABL inhibitors such as GNF-7 and ponatinib were also
4,12,18-20
skirting the bulk of Ile315 side chain.
According to the
2
1
previous work by our group , the phenyl-pyrazole derivatives
displayed good inhibitory activity to BCR-ABL kinase. Among
them, PPBA-1 (showed in Figure 2) displayed the most potent
activity with IC50 value of 14.2 nM. By the analysis of the chemi-
cal structures of PPBA-1 and ponatinib, a new series of phenyl-
pyrazole derivatives were designed as BCR-ABL kinase inhibi-
tors with the pyrazole linker between the head region and the
middle part retained and two different groups as the head region
part (imidazo[1,2-b]pyridazine group and pyrazolo[1,5-a]pyrimi-
dine group) attached as shown in Figure 2.
13
reported as Type 2 inhibitors.
Based on chemical features of the inhibitors, cocrystal struc-
tural analysis of different Type 2 third-generation inhibitors with
Figure 1. Chemical structures of typical Bcr-Abl inhibitors.
Figure 2. Design of phenyl-pyrazole heterocyclic derivatives as new BCR–ABL inhibitor.

o
o
o
Scheme 1. Reagents and conditions: (a) NaNO
h, 30-40 %; (d) 10, Pd(PPh , Na CO , dioxane / H
g) 2-bromomalonaldehyde, EtOH, reflux, 2 h, 30% (h) Bis(pinacolato)diboron, PdCl
2
, HCl, H
2
O, 0-5 C; (b) SnCl
2
·2H
2
O, HCl, H
2
O, 0-5 C, 70-75 %; (c) 2-bromomalonaldehyde, EtOH, 55-65 C,
o
2
3
)
4
2
3
2
O(3:1), reflux, 6 h, 65%; (e) Zn dust, CH
3
COOH, r.t.; 1 h; (f) (CH
3
CH
2
)
3
N, CH
2
Cl
2
, 0 C, r.t., 4 h, 70-75%;
o
(
2
(dppf), KOAc, toluene, 100 C, 5 h, 65%.
Scheme 2. Reagents and conditions: (i) Fe, NH
4
Cl, EtOH, H
, Dioxane, 100 C, 15 h, 65%; (l) 18, Pd(PPh , Na
N, CH Cl , r.t., 3 h, 80%; (o) NBS, CHCl , reflux, 2 h, 75%.
2
O, reflux, 3 h, 90%; (j) (Boc)
2
O, THF, reflux, 3 h, 90%; (k) Bis(pinacolato)diboron, KOAc,
COOH, CH Cl , r.t., 5 h, 85%; (n)
o
Pd(pph
3
)
2
Cl
2
3
)
4
2
CO , dioxane / H O(3:1), reflux, 6 h, 65%; (m) CF
3
2
3
2
2
(
CH CH
3
2
)
3
2
2
3
Inspired by combinational strategies of scaffold hopping and
ethanol, compound 9 was prepared. Compound 10 was obtained
conformational constraint based on PPBA-1 and ponatinib, a
series of 4-(pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)p-
henyl-3-benzamide derivatives and 4-(imidazo[1,2-b]pyridazin-
by the borylation reaction between 6-bromopyrazolo[1,5-a]pyri-
2
midine and bis(pinacolato)diboron catalyzed by PdCl (dppf) in
o
toluene at 100 C. After the Suzuki coupling reaction between
intermediate 4 and compound 10, 6-(1-(2-methyl-5-nitrophenyl)-
1H-pyrazol-4-yl)pyrazolo[1,5-a]py-rimidine (5) was obtained.
Through the reduction reaction of the intermediate 5 with Zn dust
in the presence of acetate acid, 4-methyl-3-(4-(pyrazolo[1,5-
a]pyrimidin-6-yl)-1H-pyrazol-1-yl)aniline (6) was produced.
Finally, the target products 7a-e were prepared by the acylation
reaction of variable substituted benzoylchlorides in anhydrous
2
-yl)-1H-pyrazol-1-yl)phenyl-3-benzamide derivatives have been
designed, synthesized and characterized. All compounds were
screened for BCR-ABL1 kinase inhibitory activity, and most of
all appeared good inhibitory activity to BCR-ABL kinase.
The synthetic route of 7a-e was illustrated in Scheme 1, and
that of 16a-i was outlined in Scheme 2. The synthetic details
were presented in Supplementary material. Compound 4 was
o
2
1
dichloromethane at 0 C in the presence of triethylamine.
prepared by the literature method. Via the ring-closure reaction
of 2-bromomalonaldehyde with 3-aminopyrazole, refluxing in

The synthetic route of 16a-i was illustrated in Scheme 2. First-
ly, amido-protecting reaction was conducted by compound 11
1
2
BCR-ABL IC50
nM)
and (Boc)
2
O
and succeeded to Miyaura-Ishiyama-Hartwig
Compd
Het
R
R
(
Borylation to product 13. Secondly, compound 14 obtained from
the Suzuki coupling reaction between the borylation product 13
and 3-bromoimidazo[1,2-b]pyridazine (18). Finally, the target
products 16a-i were prepared by the acylation reaction of varia-
7
7
a
H
H
H
H
H
4-OMe
766.6
803.7
b
4-CF
3
ble substituted benzoylchlorides in anhydrous dichloromethane at
o
0
C in the presence of triethylamine.
Preliminary structure-activity relationships (SARs) were ex-
7c
4-F
> 10000
2436.0
621.0
plored when pyrazolo[1,5-a]pyrimidine group and imidazo[1,2-
b]pyridazine were introduced as the head region group respec-
tively. As shown in Table 1, the compounds with the head region
composed of imidazo[1,2-b]pyridazine group exhibited
dramatically lower IC50 values ranging from 8.5 to 108.6 nM
against BCR-ABL1 kinase than those composed of pyrazolo[1,5-
a]pyrimidine group exceeding 621 nM. For instance, compound
7
d
7e
1
6a
3-CF
H
3
H
4-CF
H
8.5
16h (IC50= 108.6 nM against BCR-ABL1 kinase) displayed supe-
rior activity to compound 7d (IC50 = 2.4 μM against BCR-ABL1
kinase). It may be that imidazo[1,2-b] pyridazine group was bet-
ter in forming hydrogen bond or pi-pi interaction with the hinge
region. Moreover, the modification of the substituent in tail re-
gion had some effect on their bioactivities. Further investigation
about the potential influence of the tail region was made by in-
troducing different groups in phenyl ring. In the case of the head
region composed of imidazo[1,2-b]pyridazine group, the substit-
uents on 3-position of phenyl ring (such as 16a, 16e) in tail re-
gion showed better potency against BCR-ABL1 kinase than the
electron withdrawing group substituents on 4-position (such as
1
6b
3
74.1
a
1
6c
3-F
H
ND
16d
4-F
H
80.9
22.2
ND
1
6e
3-Cl
H
16b, 16d). In particular, by introducing trifluoromethyl group on
3
-position of phenyl ring, compound 16a showed the best per-
1
6f
4-OMe
4-Et
formance on BCR-ABL1 kinase inhibitory activity probably
owing to the favorable conformation to fit into the ATP bind site
of ABL protein. Interestingly, the electron donating group sub-
stituents on 4-position (16g) showed the IC50 value as low as 19.4
nM against BCR-ABL1 kinase. Finally, most of these com-
pounds (16a, 16b, 16d, 16e, 16g, 16h and 16i) displayed lower
IC50 values than the control compound Staurosporine (STSP),
especially compound 16a whose IC50 value was 14.3-fold lower
than that of STSP showing the great promising potential as novel
BCR-ABL1 inhibitors.
1
6g
H
19.4
108.6
16h
H
1
6i
H
26.07
121.8
STSP
Antiproliferative activities of the compounds are also examined
against K562 and U937 leukemia cell lines. the results were
summarized in Table 2. Consistent with their kinase inhibitory
activities, most of the compound showed promising
antiproliferative activies. For instance, the most promising com-
pound 16a strongly inhibited the proliferation of K562 and U937
a
ND : not determined.
a
Table 2. Antiproliferative assay in vitro
Compound
K562 IC50 (μM)
U937 IC50 (μM)
7
7
a
19.7
16.32
leukemia
cells
with
IC50
values
of 2nM
and
b
6.93
5.88
13.11
6.83
13.68μM,respectively, which showed more strong inhibitory
activity to K562 cells than that of control compound Imatinib and
similar to that of control compound Imatinib fof U937 cells.
Most of the compounds were tested at multiple doses to study the
viability of 293T cell, As shown in Table 3, The median cytotox-
ic concentration (CC50) showed that the tested compounds dis-
played almost no cytotoxicity.
7
e
1
6a
6b
<0.002
10.53
12.37
5.08
13.68
>20
1
16d
>20
In order to investigate the possible bonding mechanism, com-
pounds 16a and 7c were selected for docking studies. The bind-
ing mode of selected molecules was studied by autodock 4.0 with
the help of atuodockTools. BCR-ABL tyrosine kinase (PDB:3cs9)
was selected as the receptor for docking study. The best docking
conformation was selected for the analysis and the docking re-
sults were shown in Figure 3. Our docking study has suggested
1
6e
6g
>20
1
7.54
>20
1
6h
8.25
12.42
10.78
12.44
16i
<0.002
7.38
Imatinib
Table 1. Inhibitory activities of compounds 7a-e and 16a-i.
a
Values are means of at least two experiment.

Table 3. The median cytotoxic concentration (CC50) of tested
stacking interaction might be the main reason why 4-
(imidazo[1,2-b]pyridazin-2-yl)-1H-pyrazol-1-yl)phenyl-3-benza-
mide derivatives showed stronger inhibitory activities than 4-
compounds
Compound
CC50 (μM)
(pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)phenyl-3-benz-
amide derivatives.
7
7
7
a
b
e
>80
43.23
20.53
40.34
>80
In summary, we have successfully designed, synthesized and
characterized a series of 4-(pyrazolo[1,5-a]pyrimidin-6-yl)-1H-
pyrazol-1-yl)phenyl-3-benzamide derivatives and 4-(imid-azo
[1,2-b]pyridazin-2-yl)-1H-pyrazol-1-yl)phenyl-3-benzamide de-
16a
16b
16d
16e
16g
16h
rivatives. These new compounds were screened for BCR-ABL1
kinase inhibitory activity, most of them appeared good inhibitory
activity to BCR-ABL kinase. In particular, compound 16a dis-
played the most potent activity with IC50 value of 8.5 nM. The
compounds 16a and 16i displayed excellent antiproliferative ac-
tivities to K562 leukemia cells. Most of the tested compounds
showed almost no cytotoxicity in vitro against 293T cell com-
pared to the positive control imatinib. Molecular docking studies
indicated that these novel compounds fitted well with the active
site of BCR-ABL protein. The results above showed the great
promising potential of these compounds as novel BCR-ABL in-
hibitors.
>80
>80
>80
9.04
1
6i
23.80
27.54
Imatinib
that compound 16a could form hydrogen bond with the NH of
Met 318 in the hinge region of BCR–ABL (Figure 3). The amide
moiety formed two additional hydrogen bonds with E 286 and D
Acknowledgments
The authors would like to acknowledge financial support from
the Chinese Natural Science Foundation Project (21272020), the
Project of Construction of Innovative Teams and Teacher Career
Development for Universities and Colleges under Beijing Munic-
ipality (IDHT20140504) and Beijing Key Laboratory for Green
Catalysis and Separation.
381, and the trifluoromethylphenyl group bounded deeply in to
the hydrophobic pocket. Moreover, imidazo[1,2-b]pyridazine
group formed pi–pi interaction with F317 of BCR–ABL protein,
which was similar to ponatinib. The fact that compound 7c only
formed two hydrogen bond with Met 318 and E 286, and no pi-pi
9
.
Manetti, F.; Brullo, C.; Magnani, M.; Magnani, F.; Chelli, B.;
Figure 3. A and B show the binding model of inhibitor 16a and 7c to BCR-ABL protein. Oxygen atom (red stick), nitrogen atom (blue stick), H-
bond (green dash line), pi-pi stack (orange line).
Crespan, E.; Schenone, S.; Naldini, A.; Bruno, O.; Trincavelli, M.
L.; Maga, G.; Carraro, F.; Martini, C.; Bondavalli, F.; Botta, M. J.
Med. Chem. 2008, 51, 1252.
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