Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.06.084

A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat

Full text of DOI:10.1016/j.bmcl.2009.06.084

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4673–4678
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Imidazopyridine derivatives as potent and selective Polo-like kinase
(PLK) inhibitors
Yoshiyuki Sato, Yu Onozaki, Tetsuya Sugimoto, Hideki Kurihara, Kaori Kamijo, Chie Kadowaki,
*
Toshiaki Tsujino, Akiko Watanabe, Sachie Otsuki, Morihiro Mitsuya , Masato Iida, Kyosuke Haze,
Takumitsu Machida, Yoko Nakatsuru, Hideya Komatani, Hidehito Kotani, Yoshikazu Iwasawa
Banyu Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies sup-
ported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 dem-
onstrated good antitumor efficacy in xenograft nude rat model.
Received 14 May 2009
Revised 19 June 2009
Accepted 20 June 2009
Available online 25 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
PLK1
Polo-like kinase
Imidazopyridine
Polo-like kinases (PLKs) are categorized as serine-threonine ki-
nases and this family includes three kinases, PLK1, PLK2 and PLK3.
Among them, PLK1 participates in multiple steps in mitosis by
phosphorylating various substrates. Inhibition of PLK1 activity in
cancer cell causes mitotic arrest and finally induces strong cell-kill-
ing effect.1–3 It is also reported that PLK1 is overexpressed in many
clinical cancer samples, such as colon cancer, non-small cell lung
cancer and others.1,4,5 From these facts, PLK1 is thought to be a
promising target for anti-cancer drug. In fact, several pharmaceuti-
cal companies have disclosed PLK1 inhibitors.6–8 Of these, dihydr-
opteridinone derivative BI 2536 and thiophene amide GSK 461364
are being evaluated in clinical studies (Fig. 1).7,8
N O
N
N
N
O
S
N
HN
N
NH2
O
O
CF3
N
N
N
N O
H
BI 2536
GSK 461364
Figure 1. Structures of BI 2536 and GSK 461364.
Initially, we screened Merck chemical collection to identify a hit
compound for starting the PLK1 program. Unfortunately, no hit
compound with PLK1 potency (IC50) of less than 1 lM was ob-
tained. At the same time, another effort was to explore a new
structure class based on known PLK1 inhibitors by chemical mod-
ifications such as bioisosteric replacement and/or scaffold hopping.
For this purpose, benzimidazole derivative 19 disclosed by GSK was
selected as a starting point for our efforts because of its unique
structure and strong enzyme potency. Here we report the design
and SAR study of novel imidazopyridine PLK1 inhibitors.
Before starting the modification, we investigated the binding
mode of compound 1 in ATP binding pocket of PLK1.10 Com-
pound 1 was selected for the docking study in terms of simple
* Corresponding author. Tel.: +81 29 877 2222; fax: +81 29 877 2029.
E-mail address: morihiro_mitsuya@merck.com (M. Mitsuya).
Figure 2. Docking study of compound 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.084

4674
Y. Sato et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4673–4678
structure and good enzyme potency. As a result, it seemed that
Cys133 in the hinge region may interact with the nitrogen of
the benzimidazole by a hydrogen bond and the amide function
may bind to the conserved catalytic residues (Fig. 2). This infor-
mation prompted us to convert the benzimidazole into other
heterocycles which potentially bind to Cys133. Encouragingly,
pyrazolopyridine (2) and imidazopyridine (3) were found to re-
place the benzimidazole (Table 1). Deletion of the phenyl moiety
in 3 (4) resulted in the reduction in potency, suggesting that the
bicyclic aromatics could well occupy the ATP binding pocket.
Aminothiazoles (5–7) which are known as a hinge binder of
the reported kinase inhibitors,11 were also tested. However, they
completely lost PLK1 potency. Compound 3 was selected for fur-
ther modification based on the highest enzyme potency in this
series.
Table 1
Next, the effect of the substituents around the benzyl moiety
in compound 3 was investigated (Table 2). According to the pat-
ent information9 reported by GSK, ortho-substituted compounds
(3, 8) and methylated compounds (9, 10) at the benzylic position
were tested. Replacement of CF3 to Cl (8) significantly improved
cell potency12 with maintained enzyme potency. Introduction of
a methyl group with (R)-configuration (9) enhanced both en-
zyme and cell potencies. However, compound 9 suffered from
the large discrepancy between enzyme and cell potencies (44-
fold). We speculated that high liphophilicity and low aqueous
solubility of compound 9 may affect permeability, resulting in
the reduction of the cell potency. Taking the relationship be-
tween cell potency, log D value and aqueous solubility into con-
Replacement of benzimidazole
CF3
O
H2NOC
S
R
Compound
R
PLK1 (IC50
,
Solubility (
buffer
l
M)a pH 7.4
log D7.4b
l
M)
N
1
2
3
0.035
0.130
0.022
<1.0
1.2
4.6
4.8
4.2
N
N
N
sideration, compound
9 was further optimized to identify
analogs with better cell potency by incorporating hydrophilic
substituents.
N
N
Docking of compound 9 into PLK1 model led to the proposed
binding mode shown in Figure 3.10,13 In this docking model, imi-
1.2
N
S
4
5
0.430
>3.00
NT
NT
NT
NT
N
N
NH2
S
S
6
7
>3.00
2.10
NT
NT
NT
NT
N
N
N
H
O
N
H
a
Ref. 16.
Ref. 17.
b
Figure 3. Docking study between homology model of PLK1 and compound 9.
Table 2
Effect of substituents on ortho-position and benzylic position
R2
R1
O
N
H2NOC
S
N
Compound
R1
R2
PLK1 (IC50, nM)
Cella (EC50
,
l
M)
Solubility (
lM) pH 7.4 buffer
log D7.4
3
8
9
10
1
H
H
CF3
Cl
Cl
22
35
7.0
300
35
5.00
1.15
0.31
NT
1.2
1.3
<1.0
NT
<1.0
4.2
4.1
4.8
NT
4.6
(R)-Me
(S)-Me
Cl
2.00
a
Mitotic arrest in HeLaS3.

Y. Sato et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4673–4678
4675
Table 3
Profile of hydroxymethyl analogs
R1
O
H2NOC
S
R2
N
R3
N
Compound
R1
R2
H
R3
H
PLK1 (IC50, nM)
Cell (EC50
,
lM)
Solubility (
lM) pH 7.4 buffer
log D7.4
11
88
3.75
50.1
3.2
OH
O
OH
12
13
14
H
H
39
1.16
0.08
0.21
NT
26.1
13.8
1.7
3.7
3.8
4.2
4.1
Cl
O
HO
H
H
4.9
7.3
92
Cl
Cl
O
O
CH2OH
H
15a
H
CH2OH
1.7
Cl
O
a
Diastereomer mixture.
dazopyridine 1-N was found in the position to interact with the
hinge residue of Cys133, and the amide moiety was close to
Lys82 and Asp194 as observed in the docking model of compound
1. Meta- and para-positions of the benzyl group, and 5- and 6-posi-
tions of the imidazopyridine were facing towards the solvent
accessible region, suggesting that hydrophilic substituents in these
positions might be tolerated. Based on this model, we decided to
explore the best position to incorporate hydrophilic substituents
by introducing a hydroxymethyl group.
other hand, improvement in cell potency was dependent on the
nature of the amine groups such as bulkiness, lipophilicity and ba-
sicity. Especially, acyclic amines (16, 17, 18, 19, 22) exhibited bet-
ter cell potency than 13 did. Unfortunately, these compounds were
easily oxidized by air and light to generate the corresponding alde-
hyde. However, a tert-butyl group in 22 prevented the oxidation
probably due to its steric bulkiness around the amine group. More-
over, aqueous solubility of compound 22 was greatly improved
compared to 13.
The result of the solvent region-directed modification is shown
in Table 3. As expected by the modeling prediction, hydroxymethyl
analogs (13, 14) maintained PLK1 enzyme potency, while com-
pounds (11, 12, 15) decreased potency. In this modification, com-
pound 13 showed the most promising data such as enzyme
potency, cellular potency and chemical properties. Given the infor-
mation that a hydroxymethyl at the para-position of the benzyl
group in 13 may extend to the solvent region, we replaced the
hydroxymethyl group by various amines to enhance the solubility
and cell potency.
Additional enhancement in potency was observed by exploring
the ortho-substituent of the benzyloxy group in 22 (Table 5). Since
the patent information9 implied that small and lipophilic substitu-
ents such as trifluoromethyl and chloro groups were tolerable, we
replaced the chloro group in 22 by substituents with appropriate
size and lipophilicity. As a result, compound 36 with a difluorome-
thoxy group showed better enzyme and cell potencies as well as
good solubility. With these encouraging data, 36 was selected for
further evaluation.
Compound 36 displayed high selectivity for PLK1 over a panel of
212 kinases in the KinaseProfiler assays from Millipore.14 Of 212
tested kinases, only 2 isoform kinases (PLK2 and PLK3) showed
Table
4 summarizes the structure–activity relationship of
amine derivatives. The amines we tested were generally tolerable
for enzyme potency, suggesting that the solvent region accepted
a wide range of structures regardless of the properties. On the
more than 50% inhibition at 1
lM. IC50 values for PLK2, PLK3 were
21 nM and 178 nM, respectively.

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Y. Sato et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4673–4678
Table 4
Replacement of hydroxymethyl group in compound 13
R
Cl
O
H2NOC
S
N
N
Compound
R
PLK1 (IC50, nM)
4.9
Cell (EC50, nM)
Solubility (
13.8
lM) pH 7.4 buffer
log D7.4
OH
13
80
3.8
H
N
16
17
18
19
20
21
22
23
24
25
26
27
28
29a
30
16
22
21
28
12
25
21
21
19
23
13
17
27
20
12
16
36
48
>170
>170
>170
>170
14.8
>170
>170
>170
>170
>170
11.2
NT
1.9
2.9
2.8
2.3
3.6
3.5
2.9
2.4
2.1
2.9
3.7
2.8
3.3
3.3
2.8
3.2
N
H
N
37
H
N
68
H
N
220
121
48
H
N
H
N
H
N
184
219
120
400
120
390
227
1700
400
OH
H
N
OH
H
N
OH
F
N
N
N
N
OH
169
OH
>170
45.7
2.9
N
N
NH
O
SO2
31
N
a
Diastereomer mixture.

Y. Sato et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4673–4678
4677
Table 5
Effect of ortho-substituents in compound 22
H
N
R
O
H2NOC
S
N
N
Compound
R
PLK1 (IC50, nM)
Cell (EC50, nM)
Solubility (lM) pH 7.4 buffer
log D7.4
22
32
33
34
35
36
–Cl
–F
–Me
21
46
150
210
20
48
>170
>170
NT
NT
>170
>170
2.9
2.2
NT
NT
2.6
2.7
290
NT
NT
82
–CHF2
–OCHF2
9.8
19
OH
Day
0
MeO2C
MeO2C
1
2
3
6
10
13
a
b
S
I
N
N
N
:48hr, i.v. infusion
:Tumor volume measure
N
N
N
37
38
39
10
8
Scheme 1. Synthesis of compound 39. Reagents and conditions: (a) methyl
propiolate, PdCl2(PPh3)2, CuI, K2CO3, 30 °C, THF; (b) methylthioglycolate, MeONa,
MeOH, 58% in two steps.
Control
0.45 mpk/h
6
0.60 mpk/h
The synthetic route for 36 is illustrated in Schemes 1 and 2. The
preparation started with Sonogashira reaction of methyl propiolate
with 3-iodoimidazopyridine 37.15 Michael addition of methyl thio-
glycolate to 38 and subsequent intramolecular cyclization gave a
key intermediate 39 (Scheme 1). For the benzyl alcohol part, com-
mercially available 3-hydroxy-4-methylbenzoic acid (40) was used
as a starting material. Difluoromethylation of 40 followed by ester-
ification produced ester 41. Conversion of the methyl group in 41
to an aldehyde 43 was conducted in three steps. Dibromination
of the methyl group and substitution with KOAc followed by
hydrolysis provided the aldehyde 43. Methylation of 43 with Grig-
nard reagent afforded alcohol 44. Reduction of an ester group in 44,
protection of the primary alcohol and oxidation of the secondary
alcohol with SO3/pyridine gave ketone 45. Chiral reduction of the
ketone 45 using (R)-2-methyl-CBS-oxazaborolidine gave 46
(95%ee) which was treated with Lipase PS-C to enrich the optical
purity, providing enantiopure 46 (>99%ee). Mitsunobu reaction of
46 with the key intermediate 39 afforded ester 47. Treatment of
47 with methanolic ammonia and deprotection of TBS group pro-
vided amide 48. Finally, mesylation of the resulting alcohol in 48
followed by substitution with t-butylamine furnished compound
36. Other derivatives were prepared in a similar method to 36.
In summary, we identified a highly potent and selective PLK1
inhibitor 36 with an imidazopyridine scaffold based on molecular
modeling with compound 1 and following extensive chemical
modifications. In addition, compound 36 displayed good in vivo
antitumor efficacy. Thus 36 represents a potential lead for the
treatment of cancer. Further studies of this class are ongoing and
the results will be reported elsewhere.
4
2
*:P<0.05 vs control
0
0
5
10
15
Days after injection
Figure 4. In vivo antitumor efficacy of compound 36.
Table 6
Tumor growth inhibition (%) after dosing of compound 36
Plasma concentration at
48 h (nM)
Day 3
(%)
Day 6
(%)
Day 10
(%)
Day 13
(%)
0.45 mpk/
h
0.60 mpk/
h
50
80
38
74
34
78
31
69
33
68
In vivo antitumor efficacy of compound 36 was examined in
Hela-luc xenograft bearing rats (Fig. 4 and Table 6). Iv infusion of
compound 36 for 48 h demonstrated significant tumor growth
inhibition. 38% and 74% growth inhibition were observed on day
3 after infusion at 0.45 mpk/h and 0.60 mpk/h, respectively. In
addition, administration induced mild and reversible white blood
cell reduction, but did not cause severe toxicity such as body
weight loss and diarrhea.

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Y. Sato et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4673–4678
Br
CHO
c
a,b
d,e
Br
MeOOC
OCF2H
HOOC
OH
MeOOC
OCF2H
MeOOC
OCF2H
40
41
42
43
OH
O
OH
f
g,h,i
j,k
O
O
MeOOC
OCF2H
TBS
OCF2H
TBS
OCF2H
44
45
46
H
O
OH
N
TBS
OCF2H
OCF2H
O
O
OCF2H
O
O
N
O
O
N
O
H2N
H2N
m,n
o, p
l
S
S
S
N
N
N
N
47
48
36
Scheme 2. Synthesis of compound 36. Reagents and conditions: (a) SOCl2, MeOH, reflux; (b) ClF2CCOONa, K2CO3, MeCN, reflux, 58% in two steps; (c) NBS, (PhCOO)2, CCl4,
70 °C; (d) KOAc, MeCN, reflux; (e) NaOMe, MeOH/THF, rt, 81% in three steps; (f) MeMgCl, THF, À20 °C; (g) LiBH4, THF, 50 °C; (h) TBSCl, imidazole, DMF, rt; (i) SO3/pyridine,
DMSO, 70% in four steps. (j) BH3–DMS, (R)-2-methyl-CBS-oxazaborolidine, THF, 0 °C; (k) lipase PS-C, vinyl acetate, hexane, 40 °C, 69% in two steps; (l) 39, n-Bu3P, DIAD, THF,
rt; (m) NH3, MeOH, 70 °C in sealed tube; (n) TBAF, THF, rt, 85% in three steps; (o) MsCl, i-Pr2NEt, CHCl3; (p) t-BuNH2, DMSO, 68% in two steps.
11. (a) Shimamura, T.; Shibata, J.; Kurihara, H.; Mita, T.; Otsuki, S.; Sagara, T.; Hirai,
Supplementary data
H.; Iwasawa, Y. Bioorg. Med. Chem. Lett. 2006, 16, 3751; (b) Misra, R. N.; Xiao,
H.; Kim, K. S.; Lu, S.; Han, W. C.; Barbosa, S. A.; Hunt, J. T.; Rawlins, D. B.; Shan,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.06.084.
W.; Ahmed, S. Z.; Qian, L.; Chen, B. C.; Zhao, R.; Bednarz, M. S.; Kellar, K. A.;
Mulheron, J. G.; Batrorsky, R.; Roongta, U.; Kamath, A.; Marathe, P.; Ranadive, S.
A.; Sunanda, A.; Sack, J. S.; Tokarski, J. S.; Pavletich, N. P.; Lee, F. Y. F.; Webster,
K. R.; Kimball, S. D. J. Med. Chem. 2004, 47, 1719.
12. It is well-known that inhibition of PLK1 leads to mitotic arrest. Therefore,
mitotic arrest was measured to assess cell potency of the compounds. See
Supplementary data.
References and notes
13. The Conolly molecular surface of the binding pocket is colored in gold with
Molecular Operating Environment (MOE) 2006.08 (Chemical Computing Group
Inc., Montreal, Quebec, Canada)
1. Eckerdt, F.; Yuan, J.; Strebhardt, K. Oncogene 2005, 24, 267.
2. Lowery, D. M.; Lim, D.; Yaffe, M. B. Oncogene 2005, 24, 248.
3. Xie, S.; Xie, B.; Lee, M. Y.; Dai, W. Oncogene 2005, 24, 277.
4. Takai, N.; Hamanaka, R.; Yoshimatsu, J.; Miyakawa, I. Oncogene 2005, 24, 287.
5. Strebhardt, K.; Ullrich, A. Nat. Rev. Cancer 2006, 6, 321.
14. Compound 36 was tested against a panel of kinases. Notably, it had <50%
inhibition @ 1 lM against Abl, Abl(T315I), ALK, ALK4, AMPK, Arg, ARK5, ASK1,
Aurora A, Axl, Blk, Bmx, BRK, BrSK1, BrSK2, BTK, CaMKI, CaMKII, CaMKIV,
CDK1/cyclinB, CDK2/cyclinA, CDK2/cyclinE, CDK3/cyclinE, CDK5/p25, CDK5/
6. (a) Johnson, E. F.; Stewart, K. D.; Woods, K. W.; Giranda, V. L.; Luo, Y.
Biochemistry 2007, 46, 9551; (b) Hanan, E. J.; Fucini, R. V.; Romanowski, M. J.;
Elling, R. A.; Lew, W.; Purkey, H. E.; Vanderporten, E. C.; Yang, W. Bioorg. Med.
Chem. Lett. 2008, 18, 5186; (c) Fucini, R. V.; Hanan, E. J.; Romanowski, M. J.;
Elling, R. A.; Lew, W.; Barr, K. J.; Zhu, J.; Yoburn, J. C.; Liu, Y.; Fahr, B. T.; Fan, J.;
Lu, Y.; Pham, P.; Choong, I. C.; Vanderporten, E. C.; Bui, M.; Purkey, H. E.;
Evanchik, M. J.; Yang, W. Bioorg. Med. Chem. Lett. 2008, 18, 5648.
7. Warner, S. L.; Stephens, B. J.; Von Hoff, D. D. Curr. Oncol. Rep. 2008, 10, 122.
8. Rudolph, D.; Steegmaier, M.; Grauert, M.; Baum, A.; Quant, J.; Garin-Chesa, P.;
Adolf, G. R. Abstract of Papers, 20th EORTC-NCI-AACR Symposium, Geneva,
Switzland, October 2008; Abstract 430.
9. Andrews, C. W., I.; Cheung, M.; Davis-Ward, R. G.; Drewry, D. H.; Emmitte, K.
A.; Hubbard, R. D.; Kuntz, K. W.; Linn, J. A.; Mook, R. A.; Smith, G. K.; Veal, J. M.
PCT Int. Appl. WO2004014899, 2004. Recently, detailed SAR information has
been published.; (a) Emmitte, K. A.; Adjebang, G. M.; Andrews, C. W.; Badiang
Alberti, J. G.; Bambal, R.; Chamberlain, S. D.; Davis-Ward, R. G.; Dickson, H. D.;
Hassler, D. F.; Hornberger, K. R.; Jackson, J. R.; Kuntz, K. W.; Lansing, T. J.; Mook,
R. A., Jr.; Nailor, K. E.; Pobanz, M. A.; Smith, S. C.; Sung, C. M.; Cheung, M. Bioorg.
Med. Chem. Lett. 2009, 19, 1694; (b) Emmitte, K. A.; Andrews, C. W.; Badiang, J.
G.; Davis-Ward, R. G.; Dickson, H. D.; Drewry, D. H.; Emerson, H. K.; Epperly, A.
H.; Hassler, D. F.; Knick, V. B.; Kuntz, K. W.; Lansing, T. J.; Linn, J. A.; Mook, R. A.,
Jr.; Nailor, K. E.; Salovich, J. M.; Spehar, G. M.; Cheung, M. Bioorg. Med. Chem.
Lett. 2009, 19, 1018.
p35, CDK6/cyclinD3, CDK7/cyclinH/MAT1, CDK9/cyclinT1, CHK1, CHK2, CK1
c1,
CK1 2, CK1 3, CK1d, CK1, CK2, cKit(D816V), cKit, c-RAF, CSK, cSRC, DAPK1,
c
c
DAPK2, DCAMKL2, DDR2, DMPK, DRAK1, DYRK2, eEF-2K, EGFR, EGFR(L858R),
EGFR(L861Q), EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8,
EphB1, EphB2, EphB3, EphB4, ErbB4, Fer, Fes, FGFR1, FGFR2, FGFR3, FGFR4, Fgr,
Flt1, Flt3(D835Y), Flt3, Flt4, Fms, Fyn, GRK5, GRK6, GSK3
HIPK2, HIPK3, IGF-1R, IKK IKKb, IR, IRR, IRAK1, IRAK4, Itk, JAK2, JAK3,
JNK1 1, JUK2 2, JNK3, Lck, LIMK1, LKB1, LOK, Lyn, MAPK1, MAPK2, MAPKAP-
K2, MAPKAP-K3, MARK1, MEK1, Met, MINK, MKK4, MKK6, MKK7b, MLCK,
MLK1, Mnk2, MRCK , MRCKb, MSK1, MSK2, MSSK1, MST1, MST2, MST3, MuSK,
NEK2, NEK3, NEK6, NEK7, NEK11, NLK, p70S6K, PAK2, PAK3, PAK4, PAK5, PAK6,
PAR-1B , PASK, PDGFR , PDGFRb, PDK1, PhK 2, PI3-kinaseb, PI3-kinase , PI3-
kinased, Pim-1, Pim-2, PKA, PKB , PKBb, PKB , PKCa, PKCbI, PKCbG, PKC , PKCd,
PKC , PKC , PKC , PKC , PKCh, PKCf, PKD2, PKG1 , PKG1b, PRAK, PRK2, PrKX,
a, GSK3b, Hck, HIPK1,
a,
a
a
a
a
a
c
c
c
a
c
e
g
i
l
a
PTK5, Pyk2, Ret, RIPK2, ROCK-I, ROCK-II, Ron, Ros, Rse, Rsk1, Rsk2, Rsk3,
SAPK2a, SAPK2a(T106M), SAPK2b, SAPK3, SAPK4, SGK, SGK2, SGK3, SIK, SRPK1,
SRPK2, STK33, Syk, TAK1, TBK1, Tie2, TrkA, TrkB, TSSK1, TSSK2, WNK2, WNK3,
Yes, ZAP-70 and ZIPK.
15. Enguehard, C.; Renou, J. L.; Collot, V.; Hervet, M.; Rault, S.; Gueiffier, A. J. Org.
Chem. 2000, 65, 6572.
16. Dohta, Y.; Yamashita, T.; Horiike, S.; Nakamura, T.; Fukami, T. Anal. Chem. 2007,
79, 8312.
17. Nishimura, I.; Hirano, A.; Yamashita, T.; Fukami, T. J. Chromatogr., A 2009, 1216,
2984.
10. PLK1 homology model was built based on the structure of Aurora A kinase
because of high sequence homology in the ATP site.