Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases

Article abstract of DOI:10.1016/j.bmcl.2012.09.063

The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.

Full text of DOI:10.1016/j.bmcl.2012.09.063

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7169–7173
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and structure–activity relationships of a novel series of pyrimidines
as potent inhibitors of TBK1/IKKe kinases
Edward G. McIver a, , Justin Bryans a, Kristian Birchall a, Jasveen Chugh a, Thomas Drake a,
Stephen J. Lewis a, Joanne Osborne a, Ela Smiljanic-Hurley a, William Tsang a, Ahmad Kamal a,
Alison Levy a, Michelle Newman a, Debra Taylor a, J. Simon C. Arthur b, Kristopher Clark b, Philip Cohen b
⇑
a MRC Technology, Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London, NW7 1AD, UK
b The MRC Protein Phosphorylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2012
Revised 17 September 2012
Accepted 18 September 2012
Available online 28 September 2012
The design, synthesis and structure–activity relationships of a novel series of 2,4-diamino-5-cyclopropyl
pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we
have developed compounds with improved selectivity and drug-like properties. These compounds have
been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the
TBK1/IKKe pathway in inflammatory diseases.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
TBK1
IKK
TANK-binding kinase
B kinase epsilon
e
Ij
Interferon b
RANTES
Toll-like receptors (TLRs) play a key role in the activation of the
innate immune system in response to invading pathogens (e.g.
viruses, bacteria and fungi). Signalling via TLRs results in the
understanding of the physiological role of this pathway, there are
liabilities associated with it, including kinase selectivity, high
molecular weight and poor ADMET properties. We herein describe
the development of a novel series of 2,4-diamino-5-cyclopropyl
activation of IjB kinases (IKKs) which regulate transcriptional
programmes required for the production of inflammatory media-
pyrimidines as potent inhibitors of TBK1/IKKe, with improved
tors to combat the invading pathogens. The canonical IKKs activate
kinase selectivity and drug-like properties. These compounds have
been evaluated in a range of cellular and in vivo assays, and
enabled us to probe the complex biology of this pathway.
The compounds were synthesized from the appropriate
5-substituted-2,4-dichloropyrimidine intermediates according to
Scheme 1. Treatment of the appropriate ester enolate with ethyl
formate followed by condensation with thiourea in one pot gave
NF-
while the IKK-related kinases, known as TANK-binding kinase 1
(TBK1) and I B kinase epsilon (IKK ) catalyse the activation of
interferon regulatory factor 3 (IRF3).1 Phosphorylation of IRF3 by
TBK1/IKK triggers its nuclear translocation and the subsequent
expression of IRF3-dependent genes, such as interferon b (IFNb)
and RANTES.2–4 TBK1/IKK
also play an important role in restrict-
ing the extent of activation of the canonical IKKs.5,6
Although TBK1/IKK
jB leading to the production of pro-inflammatory cytokines,
j
e
e
e
e
kinases have attracted considerable inter-
est in recent years by their putative role in cancer7–9 and inflam-
matory diseases10 there have been relatively few reports of small
molecule inhibitors of this pathway.11,12 It was recently reported
that BX795 (Fig. 1), originally developed as an inhibitor of 3-phos-
phoinositide dependent protein kinase 1 (PDK1)13 was found to be
TBK1 (2 nM)
N
N
PDK1 (12 nM)
HN
N
O
HN
N
O
H
H
O
N
N
O
N
N
O
S
a potent inhibitor of the TBK1/IKK
e
pathway.14,15 Whilst this com-
NH2
N
N
H
N
N
H
H
H
pound has proved to be a useful in vitro research tool to facilitate
I
Br
BX795 (1)
BX320 (2)
⇑
Corresponding author. Tel.: +44 (0)20 8906 7237; fax: +44 (0)20 8906 7200.
E-mail address: emciver@tech.mrc.ac.uk (E.G. McIver).
Figure 1. Structures of BX795 and BX320.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.063

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E. G. McIver et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7169–7173
Table 1
Amide SAR
S
(a)
1
HN
NH
MeO2C
R
4
3
O
N
1
R
HN
N
H
O
HN
F
(b)
N
N
N
O
N
N
O
R2
R2
3
N
R
N
N
H
N
HN
H
H
H
Br
Br
TBK1 IC50 (nM)a
Cl
(9)
(10a-j)
8
(f)
N
N
R2
PDK1 IC50 (nM)a
26
N
Entry
N
H
NH2
Cl
S
1
5
R
1
9
6
R
S
(g)
10a
10b
10c
9
60
130
—
(c)
3
R
OMe
Cl
HN
(d) or (e)
N
N
O
N
N
O
CF3
450
—
2
2
R
N
N
R
N
H
N
H
H
H
1
1
R
6
R
7
10d
3600
—
N
Scheme 1. (a) i. LDA, then ethyl formate, THF, À78 °C to rt; ii. Thiourea, MeOH–THF,
reflux; 22–40% (2 steps); (b) POCl3, DIPEA, 90 °C, 75–90%; (c) NH2(CH2)3NH(CO)R2,
DIPEA, IPA, 50–77%; (d) R3NH2, AcOH, n-butanol, microwave, 150 °C, 5–76% (after
HPLC); (e) R3NH2, Pd2(dba)3, Xantphos, NaOtBu, dioxane, 2–57% (after HPLC); (f) i.
NH2(CH2)3NHBOC, DIPEA, IPA, 70%; ii. R3NH2, HCl, dioxane-water-MeCN, 50 °C, 63–
80%; (g) R2COOH, DIPEA, HATU, DMF, 6–73% (after HPLC).
O
N
10e
10f
22
—
—
N
560
the corresponding thiouracil 4, which was converted to 5 with
POCl3/DIPEA. Nucleophilic substitution of 5 with a suitably func-
tionalized 1-amino-3-amidopropane derivative occurs regioselec-
tively at the 4-position to give chloropyrimidine 6, which will
then undergo either an acid mediated displacement or Buchwald
amination with the appropriate amine to give the target molecules.
Alternatively, the amide can be varied at the last step: condensa-
tion of 5 with NH2(CH2)3NHBOC, followed by treatment with the
appropriate amine under acidic conditions to give 8. Subsequent
coupling with the appropriate carboxylic acid gave the desired
amide 7. This chemistry is amenable to parallel synthesis, and in
most cases mass-directed LCMS was utilized for purification of
the final compounds.
10g
10h
10i
8
2
220
68
—
N
N
4300
O
10j
430
—
a
Values quoted are the mean of at least two experiments with a range of <25% of
the mean value.
selectivity. This compound was also found to have poor metabolic
stability in human and mouse liver microsomes and required fur-
ther optimization.
Table 1 shows the data for a selection of analogues which were
synthesized around the 5-bromopyrimidine core. All compounds
were screened in the TBK1 radiometric assay, and the more potent
examples were also screened against PDK1.16
Using the X-ray crystal structure of BX320 (2) bound to PDK1,13
a homology model was generated for TBK1. Figure 2 illustrates a
docking of compound 10h to the ATP binding site. The model sug-
gests that the anilino pyrimidine is forming key H-bonding interac-
tions to C89 at the hinge; the 5-bromo substituent is pointing
towards the M86 gatekeeper residue; the 4-aminopropyl linker is
occupying the ribose pocket below the glycine-rich loop with the
terminal amide group pointing towards the conserved lysine
(K38). The fluorophenyl group appears to occupy a hydrophobic
pocket close to the hinge, with the 3- and 4- positions of the ring
being solvent exposed.
Replacement of the 5-iodo group with a bromine (9) was toler-
ated, however, like BX795, a modest selectivity window over PDK1
was observed. In attempt to design compounds with improved
selectivity over PDK1, we investigated replacement of the urea. A
published crystal structure of BX320 bound to PDK1 suggests that
key H-bonding interactions are formed between the urea of BX320
(2) and Glu166 and Leu88 of the protein.13 To test this hypothesis
we replaced the urea with a fluorine (10a) and were pleased to find
that TBK1 potency was maintained and the selectivity over PDK1
had increased. We then began to investigate the effect of replace-
ment of the thiophene amide, and a selection of compounds are
shown in Table 1 (10b–j). Substituted aryl amides resulted in a sig-
nificant loss of potency against TBK1. Basic functionality, such as
the N-methyl piperidine derivative (10i) was poorly tolerated,
although some activity could be restored in the acetamide (10j).
However, small cycloalkyl amides (10g–h) were found to show
optimal potency for TBK1. Moreover, the selectivity over PDK1
had improved further. Compound 10h was profiled against a panel
of 71 protein kinases (Fig. 3) and was found to have only modest
In an attempt to replace the potentially labile bromine moiety,
we investigated a range of hydrocarbon replacements (Table 2).
The homology model suggests that this group points towards the
gatekeeper residue, and we hoped that modifications may improve
the kinase selectivity profile.17 The comparatively smaller ethyl
derivative (11) resulted in a 10-fold loss in activity against TBK1,
whereas the bulkier isopropyl and cyclopropylmethyl groups lost
affinity altogether. Although the 5-cyclopropyl derivative (14)
was found to have slightly reduced activity compared to the corre-

E. G. McIver et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7169–7173
7171
cellular potency. Based on the homology model, the meta- and
para- positions appear to be solvent exposed which would provide
an opportunity to add polarity to attenuate the physicochemical
properties, as well as blocking potential sites of metabolism on
the aniline ring.
M86
K38
Table 3 shows a selection of compounds which were synthe-
sized. Selected compounds were evaluated for inhibition of LPS-
induced RANTES release in cells.18 Entries 15a–d illustrate some
important SAR which was generated on a less potent series of
2-thiophenyl amides. Ortho- substitution of the aromatic ring
resulted in loss of activity; replacement of the phenyl ring with a
cyclohexyl or a 4-fluorobenzyl derivative abolished activity alto-
gether. Substitution at the 3-position with a variety of different
groups was investigated (16a–c). These compounds maintained
activity against TBK1, moreover, there was a significant improve-
ment in the cellular potency compared to 14. 4-Substituted deriv-
atives, in general were found to be highly potent against TBK1 in
the biochemical assay, but had variable cellular activity: com-
pounds bearing basic functionality (entries 17a–c) were generally
less potent, whereas neutral substituents, such as the morpholine
17d and triazole 17e inhibited the secretion of RANTES. Unfortu-
nately, these compounds were found to have poor microsomal sta-
bility. Pyridyl derivatives were prepared (18a–c) in order to reduce
the electron density of the aniline ring. Although these compounds
were potent in the biochemical assay, they generally showed poor
cellular potency. For example, the pyridyl morpholine 18b was al-
most 10-fold less active in the RANTES assay then the correspond-
ing phenyl derivative 17d. Interestingly the pyrimidine 18d was
significantly less potent in the biochemical assay. A range of fused
bicycles were also investigated (19a–c). The highly potent tetrahy-
droisoquinoline derivative 19a unfortunately showed only modest
activity in the cellular assay. Although the more neutral indazole
derivatives (19b–c) showed improved cellular activity, these ana-
logues suffered from poor microsomal stability.
We then investigated a series of substituted pyrazole deriva-
tives (Entries 20a–j). Although the 1-methyl-3-amino pyrazole
20a was inactive against TBK1, the corresponding 4-amino pyra-
zole 20b restored activity. Moreover, this compound was found
to have reasonable cellular potency and was comparatively stable
in both human and mouse liver microsomes. The N-1 substituent
was varied with a range of hydrocarbon derivatives (20c–g), which
were all found to be highly potent in the biochemical assay, and
have reasonable potency in the RANTES assay. The tetrahydropyr-
anyl derivative 20h was tolerated in both assay formats, however,
basic substituents, such as the ethyl-morpholine 20i and piperi-
dine 20j lost activity in cells.
Hinge
C89
Solvent
Figure 2. Homology model of TBK1 complexed to compound 10h.
Table 2
5-position SAR
HN
F
O
N
N
N
N
H
H
R1
a
a
Entry
11
R1
TBK1 IC50 (nM)
PDK1 IC50 (nM)
63
—
—
12
13
>1000
>1000
8
—
14
580
a
Values quoted are the mean of at least two experiments with a range of <25% of
the mean value.
sponding bromo analogue, this compound was found to be 70-fold
selective over PDK1, and significantly more selective than 10h in
the kinase selectivity panel (Fig. 3).
Unfortunately, this compound was found to have poor stability
in human and mouse liver microsomes, which could be attributed
to its electron rich aniline moiety and high lipophilicity. Moreover
the cellular potency of this compound was poor (Table 3). Never-
theless, the promising kinase selectivity of this compound
prompted us to investigate further analogues.
A general observation on this project was that biochemically
potent inhibitors of TBK1 with basic functionality appear to have
relatively poor cellular activity compared to neutral analogues. A
likely explanation is that the basic analogues have lower cellular
permeability, which is supported by the Caco-2 data shown in
Table 4. Basic analogues 17b, 18c and 20j have a very low A > B
permeability with high efflux ratios, whereas neutral derivatives
17d, 17e and 20b have significantly improved A > B flux.
We next turned our attention to further optimize the 2-anilino
substituent, in attempt to improve the microsomal stability and
Figure 3. Kinase selectivity data on selected compounds.

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E. G. McIver et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7169–7173
Table 3
2-position SAR
R3
HN
S
R2
=
O
N
N
15
R2
N
N
H
H
14, 16-20
R2 =
a
a
Entry
R3
TBK1 IC50
(nM)
Cellular
IC50 (nM)
Microsomal
Turnoverb (%)
(h/m)
Entry
R3
TBK1 IC50
(nM)
Cellular
IC50 (nM)
Microsomal
Turnoverb (%)
(h/m)
N
N
14
8
1300
—
80/74
—
18c
18d
9
1200
—
—
—
F
F
N
15a
110
3200
N
N
15b
15c
820
—
—
—
—
19a
19b
7
570
380
91/86
42/40
F
F
N
N
>10000
16
N
N
15d
16a
16b
>10000
11
—
—
19c
20a
20b
7
90
—
86/41
—
N
N
O
560
580
26/34
—
>1000
N
N
N
28
8
170
0/21
N
O
O
N
N
N
N
N
16c
17a
3
2
88
63/—
—
20c
20d
4
7
81
61/41
37/54
N
N
Inactive
140
N
N
N
N
N
N
N
17b
17c
17d
6
8
6
550
660
58
—
20e
20f
20g
10
2
130
220
93
32/24
61/61
67/59
N
N
N
N
N
23/30
18/53
N
O
4
N
N
17e
18a
3
150
23/35
—
20h
20i
2
9
280
25/33
46/68
O
N
N
N
N
O
13
>1000
9000
N
N
N
N
N
O
18b
15
490
15/92
20j
7
3000
24/42
N
The mean value of at least two experiments is given.
a
Values quoted are the mean of at least two experiments with a range of <25% of the mean value.
Values quoted relate to in vitro microsomal turnover following 40 min incubation with human (h), or 30 min incubation with mouse (m) liver microsomes.
b
Key compounds were tested against a panel of 72 protein
kinases at 1 M. Figure 3 shows a heatmap illustrating the results.
Both BX795 (1) and 10h appear to hit a significant number of
a cyclopropyl appears to significantly improve the selectivity.
Compounds 17d and 20b, which exhibit good cellular potency
appear to be selective against the kinase panel. The progressive in-
crease in the Gini coefficient19 also demonstrates the improvement
l
kinases in the panel. Replacement of the 5-bromo-substituent with

E. G. McIver et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7169–7173
7173
Table 4
toxicity in vivo at higher doses (P20 mg/kg ip). We are currently
attempting to improve the pharmacokinetics of the series as well
as trying to understand the reasons for the observed toxicity.
In summary, we have identified a novel series of potent, selec-
Caco-2 permeability data on a selection of compounds
Compound
Caco-2 A > B (nm/s)a
Efflux ratiob
17b
18c
20j
17d
17e
20b
10
1
14
340
100
74
56
780
16
1
3
8
tive inhibitors of the TBK1/IKKe pathway. Compound 20b shows
a significant inhibition of LPS-induced release of the pro-inflamma-
tory cytokine, IFN-b in mice, although toxicity was observed at
higher doses. This chemical series has delivered a number of useful
probe compounds, which are enabling us to elucidate the putative
a
A > B values quoted relate to the apical to basolateral flux.
The efflux ratio is the (B > A)/(A > B).
role of the TBK1/IKKe pathway in inflammation.
b
Acknowledgments
Table 5
The authors would like to acknowledge Hilary McLauchlan and
James Hastie of MRC Protein Phosphorylation unit for coordinating
and running the kinase selectivity assays. In vitro microsomal sta-
bility assays were run by David Tickle and Sadhia Mahmood of
MRCT. The Caco-2 assay was carried out by BioFocus DPI. The PK
study was carried out by Pharmidex.
IC50 data for a selection of kinases
Kinase
IC50
(l
M)
20b
20
0.02
1.4
3.7
0.008
Kinase
IC50
17d
(
l
M)
17d
20b
MNK1
MARK3
VEG-FR
BRSK2
TBK1
19
Aurora B
CDK2
AMPK
PDK1
0.70
0.63
0.55
0.83
0.03
0.19
0.11
1.8
0.78
0.10
0.012
3.6
1.9
References and notes
0.006
IKKe
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2. Fitzgerald, K. A.; McWhirter, S. M.; Faia, K. L.; Rowe, D. C.; Latz, E.; Golenbock, D.
T.; Coyle, A. J.; Liao, S. M.; Maniatis, T. Nat Immunol. 2003, 4, 491.
3. Sankar, S.; Chan, H.; Romanow, W. J.; Li, J.; Bates, R. J. Cell. Signal. 2006, 18, 982.
4. RANTES stands for: Regulated on Activation Normal T cell Expressed and
Secreted.
5. Clark, K.; Peggie, M.; Plater, L.; Sorcek, R. J.; Young, E. R. R.; Madwed, J. B.;
Hough, J.; McIver, E. G.; Cohen, P. Biochem. J. 2011, 434, 93.
6. Clark, K.; Takeuchi, O.; Akira, S.; Cohen, P. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
17093.
Table 6
Pharmacokinetic data for compound 20b
Route
t1/2 (h)
Cl (ml/min/kg)
Vdis (L/kg)
1.79
F (%)
iv (1 mg/kg)
po (5 mg/kg)
0.45
1.25
79
—
—
25
7. Barbie, D. A.; Tamayo, P.; Boehm, J. S.; Kim, S. Y.; Moody, S. E.; Dunn, I. F.; Schinzel,
A. C.; Sandy, P.; Meylan, E.; Scholl, C.; Froehling, S.; Chan, E. M.; Sos, M. L.; Michel,
K.; Mermel, C.; Silver, S. J.; Weir, B. A.; Reiling, J. H.; Sheng, Q.; Gupta, P. B.;
Wadlow, R. C.; Le, H.; Hoersch, S.; Wittner, B. S.; Ramaswamy, S.; Livingston, D.
M.; Sabatini, D. M.; Meyerson, M.; Thomas, R. K.; Lander, E. S.; Mesirov, J. P.; Root,
D. E.; Gilliland, D. G.; Jacks, T.; Hahn, W. C. Nature 2009, 462, 108.
8. Ou, Y.; Torres, M.; Ram, R.; Formstecher, E.; Roland, C.; Cheng, T.; Brekken, R.;
Wurz, R.; Tasker, A.; Polverino, T.; Tan, S.; White, M. A. Cell 2011, 41, 458.
9. Boehm, J. S.; Zhao, J. J.; Yao, J.; Kim, S. Y.; Firestein, R.; Dunn, I. F.; Sjostrom, S. K.;
Garraway, L. A.; Weremowicz, S.; Richardson, A. L.; Greulich, H.; Stewart, C. J.;
Mulvey, L. A.; Shen, R. R.; Ambrogio, L.; Hirozane-Kishikawa, T.; Hill, D. E.;
Vidal, M.; Meyerson, M.; Grenier, J. K.; Hinkle, G.; Root, D. E.; Roberts, T. M.;
Lander, E. S.; Polyak, K.; Hahn, W. C. Cell 2007, 1065, 129.
10. Hammaker, D.; Boyle, D. L.; Firestein, G. S. Rheumatology 2012, 51, 610.
11. Wang, T.; Block, M. A.; Cowen, S.; Davies, A. M.; Devereaux, E.; Gingipalli, L.;
ohannes, J.; Larsen, N. A.; Su, Q.; Tucker, J. A.; Whitston, D.; Wu, J.; Zhang, H.;
Zinda, M.; Chuaqui, C. Bioorg. Med. Chem. Lett. 2012, 22, 2063.
Figure 4. In vivo efficacy of compound 20b.
12. Bamborough, P.; Christopher, J. A.; Cutler, G. J.; Dickson, M. C.; Mellor, G. W.;
Morey, J. V.; Patel, C. B.; Shewchuk, L. M. Bioorg. Med. Chem. Lett. 2006, 16, 6236.
13. Feldman, R. I.; Wu, J. M.; Polokoff, M. A.; Kochanny, M. J.; Dinter, H.; Zhu, D.;
Biroc, S. L.; Alicke, B.; Bryant, J.; Yuan, S.; Buckman, B. O.; Lentz, D.; Ferrer, M.;
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14. Clark, K.; Plater, L.; Peggie, M.; Cohen, P. J. Biol. Chem. 2009, 284, 14136.
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16. Biochemical IC50 determinations against various kinases were carried out
using radioactive (33P-ATP) filter capture assays. Compounds were incubated
over a concentration range with the kinase, a peptide substrate and radioactive
in selectivity. Table 5 shows the IC50 data for 17d and 20b against
the kinases which showed activity in the selectivity screen. Both
compounds show activity against IKKe, although the potency ap-
pears to be lower than TBK1. With the exception of MARK3, the
compounds show at least 10-fold selectivity over TBK1 against
all of the other kinases tested.
The N-methyl pyrazole analogue 20b was selected for evalua-
tion in vivo as this compound had the best overall balance of cel-
lular potency, kinase selectivity and in vitro ADME properties.
Pharmacokinetic data in CD-1 mice for this compound are summa-
rized in Table 6. The compound was found to have high clearance
and moderate oral bioavailability and a relatively short half-life.
For this reason we chose an intraperitoneal route of administration
for the in vivo model.
ATP. The reaction was stopped and the labeled substrate captured on
a
nitrocellulose filter plate and counted. The IC50 was then determined from the
compound concentration curve.
17. Tanramluk, D.; Schreyer, A.; Pitt, W. R.; Blundell, T. L. Chem. Biol. Drug. Des.
2009, 14, 16.
18. RAW264.7 murine macrophages were pre-incubated with compounds for
30 min, prior to stimulation with LPS for 6 h. Conditioned medium was assayed
for RANTES using a commercial ELISA kit.
19. Graczyk, P. P. J. Med. Chem. 2007, 50, 5773.
20. Mice were injected intraperitonealy with the compound 20b (15 mg/kg) and
30 min later LPS (3 mg/kg) was administered in the same way. Serum was
collected 1 h post-LPS challenge and the concentrations of IFNb were measured
using an ELISA assay. Data are presented as the mean SEM (n = 4). ND is non-
detectable.
Compound 20b shows a significant inhibition of LPS-induced
release of the pro-inflammatory cytokine, IFN-b in mice, (Fig. 4),20
suggesting that the TBK1/IKK
e pathway plays an important role in
inflammation. It should be noted however, that we observed acute