The discovery of thienopyridine analogues as potent IκB kinase β inhibitors. Part II

Article abstract of DOI:10.1016/j.bmcl.2009.08.054

An SAR study that identified a series of thienopyridine-based potent IκB Kinase β (IKKβ) inhibitors is described. With focuses on the structural optimization at C₄ and C₆ of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C₄, whereas polar groups with proper orientation at C₆ efficiently enhance compound potency. The most potent analogues inhibit IKKβ with IC₅₀s as low as 40 nM, suppress LPS-induced TNF-α production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-κB reporter gene assay, demonstrating that they directly interfere with the NF-κB signaling pathway.

Full text of DOI:10.1016/j.bmcl.2009.08.054

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5547–5551
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery of thienopyridine analogues as potent IjB kinase b inhibitors.
Part II
*
Jiang-Ping Wu , Roman Fleck, Janice Brickwood, Alison Capolino, Katrina Catron, Zhidong Chen,
Charles Cywin, Jonathan Emeigh, Melissa Foerst, John Ginn, Matt Hrapchak, Eugene Hickey,
Ming-Hong Hao, Mohammed Kashem, Jun Li, Weimin Liu, Tina Morwick, Richard Nelson, Daniel Marshall,
Leslie Martin, Peter Nemoto, Ian Potocki, Michel Liuzzi, Gregory W. Peet, Erika Scouten, David Stefany,
Michael Turner, Steve Weldon, Clare Zimmitti, Denise Spero, Terence A. Kelly
Research and Development, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, CT 06877, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An SAR study that identified a series of thienopyridine-based potent IjB Kinase b (IKKb) inhibitors is
Received 21 July 2009
Revised 10 August 2009
Accepted 12 August 2009
Available online 15 August 2009
described. With focuses on the structural optimization at C4 and C6 of structure 1 (Fig. 1), the study
reveals that small alkyl and certain aromatic groups are preferred at C4, whereas polar groups with proper
orientation at C6 efficiently enhance compound potency. The most potent analogues inhibit IKKb with
IC50s as low as 40 nM, suppress LPS-induced TNF-
selectivity profiles, and are active in a HeLa cell NF-
directly interfere with the NF- B signaling pathway.
a production in vitro and in vivo, display good kinase
jB reporter gene assay, demonstrating that they
Keywords:
Thienopyridine
IkB Kinase b
IKKb
j
Ó 2009 Elsevier Ltd. All rights reserved.
Inhibitors
The NF-
broad range of biological processes, including immune responses
and cell growth.1 Activated NF-
B induces the expression of a large
number of pro-inflammatory genes, including those encoding che-
mokines, cytokines, and cell adhesion molecules. NF- B also acti-
j
B family of transcription factors plays a major role in a
bility for further improvement. This profile, coupled with a struc-
ture amenable to chemical modification, encouraged us to
further pursue this class of IKKb inhibitors in a lead optimization
program. In this Letter, we report the SAR studies that led to the
discovery of a series of potent IKKb inhibitors based on structure 1.
Early exploratory studies had revealed that substitutions of
moderate sizes at C4 and C6 positions of structure 1 are tolerated,
while modifications at C5 and the 2,3-aminoamide moieties gener-
ally reduce compound potency.5 We therefore decided to focus on
C4 and C6 of structure 1.
Compounds 21–24 in Table 1 were synthesized according to
Scheme 1. Treatment of 2-chloro-3-cyano-4-methoxypyridine
(2)6 with HBr in acetic acid followed by alkylation gave a 2:1
mixture of 2-bromo and 2-chloro pyridyl ethers 3a and 3b. The
mixture of 3a and 3b was then reacted with 2-mercaptoacetamide
and NaH to give the thienopyridyl derivative 4.
j
j
vates genes whose protein products control growth responses
and suppress apoptotic pathways.
I
j
B kinase (IKK) is an enzyme complex critical for the activation
of the NF-
j
B pathway.2 IKKb, one of the catalytic subunits in the
IKK complex, has been identified as essential for the activation of
the complex in response to inflammatory stimuli.2 The potential
for utilizing IKKb inhibitors as treatment for cancer and immuno-
logical disorders has been widely recognized and actively pursued
by the pharmaceutical industry, as evidenced by a plethora of pub-
lications and patent applications in recent years.3,4
In a previous paper, we reported a lead identification process
that identified a class of IKKb inhibitors characterized by a thieno-
pyridine core (Fig. 1).5 These compounds exhibited moderate activ-
Compounds 25–33 in Table 1 were prepared according to
Scheme 2. Reaction of compound 57 with 2-cyanothioacetamide
ity in an IKKb enzyme assay (IC50 = 2–20
lM) and showed marginal
B luciferase reporter gene assay.12a Pre-
R4
cellular activity in an NF-
j
NH2
4
3
liminary SAR revealed that aliphatic substitutions of moderate
O
5
2
sizes at C4 and C6 of structure 1 are tolerated, indicating the possi-
R6
N
S
NH2
6
1
* Corresponding author. Tel.: +1 203 798 4982; fax: +1 203 791 5875.
E-mail address: jiang_ping.wu@boehringer-ingelheim.com (J.-P. Wu).
Figure 1. Thienopyridine-based IKKb inhibitors.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.08.054

5548
J.-P. Wu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5547–5551
Table 1
SMe
Structure–activity-relationship at C4 position
O
S
CN
SH
a
b
R4
S
NH2
4
N
6
O
5
6
R6
N
S
NH2
Ar
N
S
NH2
NH2
c
O
O
Compd
R4
R6
IKKb IC50 (lM)
S
NH2
16a
17a
18a
19a
20a
21
H
Me
Me
Me
Me
Me
Me
H
12.7b
S
NH2
N
2.7 0.4
1.3 0.1
2.5 0.2
13.5 0.7
4.7 0.2
2.0 0.2
2.2 0.2
7
9
Pr
iBu
Scheme 2. (a) 2-Cyanothioacetamide, NaOiPr, HOiPr, reflux, 95%; (b) 2-bromoacet-
amide, NaOMe, MeOH, reflux, 41%; (c) Ar-B(OH)2 (8), Pd2dba3/Cu(I)TC, (o-furyl)3P,
THF, 60 °C, 30–40%.
CH2OH
OMe
OEt
OPr
22
23
H
H
OMe
24
H
10.8 0.2
O
O
R4
R4
CN
SH
CN
S
O
25
Me
1.1 0.2
a
b
NH2
O
N
H
O
N
H
O
S
26
27
28
29
30
31
32
33
Me
Me
Me
Me
Me
Me
Me
Me
16.9 1.1
2.0 0.7
6.0 1.0
7.4 0.5
8.5 2.3
14.0b
10a, R4 = Me;
10b, R4 = n-Pr
11a, R4 = Me;
11b, R4 = n-Pr
R4
R4
N
N
NH2
c
O
O
S
NH2
R'O
N
S
NH2
R'O
N
12
13
R4
R4
NH2
11a
or
11b
d
e
O
O
CN
S
R1
S
NH2
NH2
N
N
TfO
N
R2
15
14
CH3
Cl
Scheme 3. (a) BrCH2C(O)NH2, K2CO3, DMF, 70 °C, 80%; (b) R’Br, K2CO3, DMF, 70 °C;
(c) Na2CO3, DMF, 100 °C; 50–70%, two steps; (d) Tf2NPh, iPr2NEt, dioxane, rt, 90%;
(e) R1R2NH2, DMF, 100 °C then Na2CO3, DMF, 100 °C, 50–80%.
Table 2
1.3 0.2
>20
SO2CH3
OH
Structure–activity-relationship at C6
CH3
NH2
O
6
R6
S
NH2
a
N
For synthesis of compounds 16–20, see Ref. 5.
Result of single test.
b
Compd
R6
IKKb IC50 (lM)
34
35
36
37
38
HO(CH2)2O
HO(CH2)3O
HO(CH2)2N
H2N(CH2)2O
H2N(CH2)3O
6.6 0.4
5.1 0.1
5.8 0.3
2.9 0.1
>50
OR
N
O
N
OR
N
NH2
O
CN
X
CN
Cl
a, b
c
S
NH2
39
40
2.4 0.0
2.5 0.1
N
3a, X = Br;
3b, X = Cl.
(3a:3b ~ 2:1)
4
2
O
N
Scheme 1. (a) 30% HBr/AcOH, 100 °C, ꢀ60%; (b) NaH, RBr, DMF, 60 °C, 20–60%; (c)
HSCH2C(O)NH2, NaH, DMF, 60 °C, 40–60%.
N
41
42
2.4 0.2
HO
HO
produced thiopyridine derivative 6. Compound 6 was then reacted
with 2-bromoacetamide in the presence of sodium methoxide to
give the thienopyridine derivative 7. Cross coupling of thioether
7 with an arylboronic acid (8) using Pd–Cu catalyst8 gave the 4-aryl
derivative 9.
0.75 0.02
0.68 0.03
N
43
HN
N
Scheme 3 outlines the synthesis of the compounds in Tables 2
and 3. Compound 10a or 10b, prepared according to literature pro-
aResult from single test.

J.-P. Wu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5547–5551
5549
M)
Table 3
Table 3 (continued)
Structure–activity-relationship at C6
Compd
R6
IKKb IC50 (l
n-Pr
NH2
O
N
H2N
62
0.50 0.07
6
R6
N
S
NH2
N
N
Compd
R6
IKKb IC50 (lM)
63
64
65
0.072 0.001
N
H
N
44
0.57 0.08
0.28 0.07
0.12 0.00
0.68a
HO
HO
0.63a
45
46
47
48
N
NH2
HN
O
N
O
0.14 0.01
N
HN
N
a
0.041 0.002
0.12 0.02
0.68 0.14
0.52 0.01
2.0 0.4
H2N
N
Results of single test.
b
The absolute stereochemistry of 57 and 58 was not determined.
H
N
49
50
51
52
N
N
cedures,9 was reacted with 2-bromoacetamide to give the corre-
sponding thioether 11a or 11b. Thioether 11a or 11b was then re-
acted with an alkyl bromide R0Br to provide the alkoxy
intermediate 12, which was directly treated with Na2CO3 to give
compound 13. Alternatively, 11a or 11b was converted into triflate
14 by reaction with bis(trifluoromethanesulfonyl)aniline. Triflate
14 was subsequently reacted with an amine followed by Na2CO3
to give the 6-aminothienopyridine derivatives 15.
We started our SAR studies at the C4 position. A series of com-
pounds with various aliphatic and aromatic substitutions at C4 po-
sition were prepared and tested in the IKKb enzyme assay.12a As
shown in Table 1, most of the compounds gave IC50s of 1–15 lM
in the enzyme assay, showing no clear SAR trends. Among the best
N
Me
N
N
O
HN
N
O
N
53
54
55
56
57b
58b
59
60
61
1.3 0.1
0.15 0.01
7.8a
H2N
analogues, C4-propyl analogue 18 and C4-furyl derivative 25 dis-
played IC50’s of about 1 lM.
O
N
N
At the C6 position, previous SAR revealed that unfunctionalized
alkyl groups were tolerated but resulted in flat SAR.5 This steered
us to explore the effects of polar functional groups. With a methyl
group fixed at C4 position, hydroxyalkyl and aminoalkyl substitu-
tions were introduced at the C6 position (Table 2). Compounds
34–38, in which the polar groups were attached to flexible ali-
phatic chains, did not show improvement in potency over those
with unfunctionalized C6 substitutions. When certain polar groups
were attached to six-membered rings, a modest improvement in
potency was observed. Compound 42, with a 40-hydroxypiperidyl
H2N
O
N
H3C
O
H
N
N
O
0.098 0.011
0.042a
S
O
*
HO
HO
HO
HO
N
group at C6, gave an IC50 of 0.75
the C6-piperidyl analogue 39. Compound 43, which contains C6-
piperazinyl group, also showed better potency (IC50 = 0.68 M).
lM, three times more potent than
l
Compound 41, the C6-(30-hydroxypiperidyl) analogue, did not
show any improvement compared to the C6-piperidyl analogue
39, revealing an orientation effect of the functional groups. It ap-
pears that the amino and hydroxyl groups in compounds 42 and
43 are engaged in polar interactions.
*
0.24a
N
N
1.45 0.05
1.95 0.05
0.59 0.01
Having identified C6 substitutions that improved the enzyme
potency, we next incorporated the C4-propyl group to determine
if we could further increase the potency. As shown in Table 3,
compounds 44–46 displayed better potency compared to their
C4-methyl analogues 41–43. Therefore, an n-propyl group was
maintained at the C4 position for further C6 SAR.
Subsequent SAR studies were directed toward understanding
and further optimizing the polar interaction(s) around C6 (Table
3). Methylation of the OH group in 45 reduced compound potency
N
N
H2N

5550
J.-P. Wu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5547–5551
The stereoselective nature of the interactions around C6 was re-
vealed by two enantiomers 57 and 58. Compound 57 gave an IC50
of 0.042 M, whereas its enantiomer 58 was five times less potent
(IC50 = 0.24
M).10
l
l
Analogues with different ring sizes were also examined (59–
65). While some seven-membered ring analogues are comparable
to their six-membered counterparts (63), five-membered ring
derivatives are less active (compounds 59–62).
An IKKb homology model11 provided structural insight into the
interactions around the C6 region. As shown in Figure 2, this region
is lined with polar amino acid residues, providing opportunities for
polar–polar interactions. The presence of the acidic residues aspar-
tate and glutamate suggest the possibility of acid–base interactions.
Selected compounds were further evaluated for their ability to
inhibit TNF-
are shown in Table 4. In a human whole blood assay,12b com-
pounds 44–46 and 48 reduced LPS-stimulated TNF- production,
with IC50’s between 1 and 10 M. In a mouse model of LPS-stimu-
lated TNF-
production,12c compounds 44–46 showed inhibitory
effects at 30 mg/kg (oral dosing). Compound 48, the most potent
compound in the enzyme and cellular assay, was active at
100 mg/kg but not at 30 mg/kg. The lower in vivo efficacy of com-
pound 48 was attributed to its poor pharmacokinetic properties as
a production in cells and in mice. Some of the results
Figure 2. Homology model of the IKKb/ATP binding site. Compound 48 is shown.
a
l
a
(47, IC50 = 0.68
H-bond donor.
(IC50 = 0.041 M) was sevenfold more potent than compound 45,
indicating a possible acid–base interaction. Mono-methylation of
the NH2 group in 48 decreased potency (49, IC50 = 0.12 M), and
di-methylation further lowered activity (50, IC50 = 0.68 M). Simi-
l
M), suggesting that the OH in 45 might be a
The analogue 48
40-aminopiperidyl
l
l
indicated by a low plasma level (0.02 lM at 30 mg/kg, 120 min
post-dosing).13 Efforts aimed at improving PK properties will be re-
ported in subsequent publications.
l
larly, methylation of the NH group in the pyrazinyl analogue 46
also reduced potency (compare 46, and 51). It appears that in addi-
tion to possible acid–base interactions, the presence of H-bond do-
nors in 48 and 46 contribute to compound activities.
Other modifications involved substituting the OH group in 45
with other functional groups. The amide/urea/ester analogues
53–55 are less potent, whereas the sulfonamide analogue 56
Kinase selectivity is a general concern with any kinase inhibitor.
For IKKb inhibitors, a specific issue concerns the selectivity against
IKK
itors, selected compounds were tested against IKK
threonine kinases and 14 tyrosine kinases.15 In the IKK
compound 48 gave an IC50 of 0.090 M, merely twofold less potent
a.
14 To assess the selectivity of the current series of IKKb inhib-
a
and 29 serine/
a
assay,
l
(IC50 = 0.098
lM) has similar potency compared to the amino ana-
than its activity against IKKb, while 44–46 displayed better selec-
logue 48. The piperazonyl anologue 52, in which the nitrogen atom
tivity (>28-fold). In the serine/threonine screen, at concentration
is non-basic, is less potent (IC50 = 2.0 lM).
of 10 lM, none of the compounds in Table 5 inhibited any of the
Table 4
Cellular and in vivo profiles (selected compounds)
Compd
hu. wh. blood
% Inhib. LPS-induced TNF-
a
in mice and plasma levelsb
30 mg/kg
(
l
M, in parentheses)
a
IC50
13.0
9.8
(lM)
100 mg/kg
10 mg/kg
44
45
46
48
93 (22.5 1.4)
p = 0.001
98 (42.3 5.2)
p = 0.0007
74 (3.5 1.5)
p <0.05
81 (2.8 0.2)
p = 0.0006
67 (3.1 0.3)
p <0.05
94 (15.5 1.3)
p <0.05
14c (0.17)
42 (1.6)
p <0.05
3.2
35 (<0.01)
p <0.05
12c (<0.01)
1.6
14c (0.02)
—
17c (<0.01)
—
a
b
c
Values are means of at least two experiments. Standard deviations are typically within 50% of reported value.
120 min post-dosing.
Not significant.
Table 5
Kinase selectivity and action mechanism
Compd
IKKb IC50
(l
M)
IKKa
IC50
(lM)
Hit against Ser/Tyr kinasesa
Hit against Tyr kinasesb
Hela NFjB (lM)
44
45
46
48
0.57 0.08
0.28 0.07
0.12 0.00
13.3 0.7
11.2f
3.4 0.3
0
0
0
0
0
6.1 0.6
5.3 1.9
7.5 0.7
1.5 0.2
2c
1d
1e
0.041 0.002
0.090 0.008
a
b
c
d
e
f
Number of serine/threonine kinases inhibited at 50% POC or less at 10
l
M. 29 Serine/threonine kinases were screened.
Number of tyrosine kinases inhibited at IC50 <10
lM. 14 Tyrosine kinases were screened.
Compound 45 hit HEK at 9
Compound 46 hit HEK at 8
Compound 52 hit HEK at 7
Result from single test.
l
l
l
M, TrkA at 8 lM.
M, PDGFRa at 0.3
M.
lM.

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kinases at 50% POC (percent of control) or less. For the tyrosine ki-
nase panel, with the exception that compound 46 inhibits PDGFR
at 0.3 M (IC50), no other kinases were inhibited at IC50’s below
M. Overall, these compounds demonstrated excellent kinase
a
l
7
l
selectivity profiles (Table 5, columns 3–5).
Another issue relates to the mechanism by which these com-
pounds inhibit TNF
nisms other than interference with the NF-
mechanistic verification, compounds 44–46 and 48 were tested
in a HeLa cell NF- B reporter gene assay, a cellular assay specific
for the NF-
B pathway.12a In this assay, compounds 44–46 and
48 gave IC50’s in the low micromolar range, indicating that they in-
deed interfere with the NF- B pathway (Table 5, column 6).
a
production, which could be due to mecha-
jB pathway. As a
j
j
j
To summarize, we have identified a series of potent IKKb inhib-
itors from the thienopyridine structural class. These compounds
inhibit IKKb in the low nanomolar range, suppress LPS-induced
5. Morwick, T.; Berry, A.; Brickwood, J.; Cardozo, M.; Katrina Catron, K.; DeTuri,
M.; Hrapchak, M.; Jacober, S.; Jakes, S.; Kaplita, P.; Ksiazek, J.; Liuzzi, M.;
Magolda, R.; Marshall, D.; McNeil, A.; Prokopowicz, A., III; Sarko, C.; Scouten, E.;
Sledziona, C.; Watrous, J.; Wu, J.-P.; Cywin, C. J. Med. Chem. 2006, 49, 2898.
6. Mittelbach, M. et al Arch. Pharm. (Weinheim Ger.) 1985, 318, 481.
7. Dimethylthiovinylketone 5 was prepared according to a literature procedure.
See Spitzner, R.; Menzel, M.; Schroth, W. Synthesis 1982, 3, 206–210.
8. Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.
TNF-
a
production in human whole blood and in mice (oral dosing),
and a range of ser-
and have good selectivity profiles against IKK
a
ine/threonine and tyrosine kinases. In addition, they demonstrate
activity in a cell based reporter gene assay dependent upon signal-
ing through NF-jB, showing that these compounds directly inter-
fere with the target pathway.
9. (a) Ratemi, E. S.; Namdev, N.; Gibson, M. S. J. Heterocycl. Chem. 1993, 30, 1513;
(b) Sharaf, S. M.; El-Sadany, S. K.; Hamed, E. A.; Youssef, A.-H. A. Can J. Chem.
1991, 69, 1445.
10. The two enantiomers 57 and 58 were obtained by chiral HPLC resolution of the
racemic material, each >98% ee. The absolute stereochemistry for each
compound was not determined.
11. An IKKb homology model was generated using the MODELLER program with
five kinase X-ray structures as templates, including the structures of CDK2,
PHK, LCK, JNK, and CPK (cAMP dependent protein kinase).
References and notes
1. (a) Barnes, P.; Karin, M. N. Engl. J. Med. 1997, 336, 1066; (b) Karin, M.; Cao, Y.;
Greten, F. R.; Li, Z. W. Nat. Rev. Cancer 2002, 2, 301; (c) Barkett, M.; Gilmore, T.
D. Oncogene 1999, 18, 6910; (d) Baeuerle, P. A.; Baltimore, D. Cell 1996, 87, 13.
2. Karin, M. Oncogene 1999, 18, 6867.
3. A selection of patents and patent applications claiming IKK inhibitors is listed
below: WO0158890(A1); US20020107252; WO03010163; WO03010158;
WO04063185; WO04063186; WO0130774(A1); WO0100610; WO0168648;
WO04022553; WO04022057; US2004116494; WO03039545; WO2004022553;
US2005049265; WO0224679(A1); US6562811; WO0244153(A1); WO03076447
(A1); WO03076447; US6869956; WO05011609; WO02094813; WO0246170;
WO0246171; WO0230353; WO0230423(A1); WO030866309(A2); WO0241843
(A2); WO03040131(A1); WO03048152(A2).
4. (a) Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Kadono, H.; Masuda, T.;
Shimazaki, M.; Shintani, T.; Fuchikami, K.; Sakai, K.; Inbe, H.; Takeshita, K.; Niki,
T.; Umeda, M.; Bacon, K. B.; Ziegelbauer, K. B.; Lowingera, T. B. Bioorg. Med.
Chem. Lett. 2003, 13, 913; (b) Murata, T.; Shimada, M.; Kadono, H.; Sakakibara,
S.; Yoshino, T.; Masuda, T.; Shimazaki, M.; Shintani, T.; Fuchikami, K.; Bacon, K.
B.; Ziegelbauer, K. B.; Lowinger, T. B. Bioorg. Med. Chem. Lett. 2004, 14, 4013; (c)
Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Masuda, T.; Shintani, T.;
Sato, H.; Koriyama, Y.; Fukushima, K.; Nunami, N.; Yamauchi, M.; Fuchikami,
K.; Komura, H.; Watanabe, A.; Ziegelbauer, K. B.; Bacon, K. B.; Lowinger, T. B.
Bioorg. Med. Chem. Lett. 2004, 14, 4019; (d) Burke, J. R.; Pattol, M. A.; Gregor, K.
R.; Brassil, P. J.; MacMaster, J. F.; McIntyre, K. W.; Yang, X.; Iotzova, V. S.; Clarke,
12. (a) The protocols for IKKb inhibition and the HeLa NF-
are described in reference 5.; The procedure for human whole blood LPS–TNF
assay has been described, see (b) Regan, J. et al J. Med. Chem. 2003, 46, 4676;
The mouse LPS/TNF- assay was performed according to procedure
jB reporter gene assay
a
a
a
previously described, except that mice were pre-dosed with test compounds
60 min prior to LPS challenge, see (c) Regan, J. et al J. Med. Chem. 2002, 45, 2994.
13. The possibility that the compound decomposed in plasma was ruled out by a
plasma stability study.
14. IKK
development of lymphoid organs and inflammatory resolution. It is generally
considered desirable to avoid inhibiting IKK in developing IKKb inhibitors.
a is one of the catalytic subunits in the IKK complex with roles in
a
See: (a) Hayden, M. S.; Ghosh, S. Genes Dev. 2004, 18, 2195; (b) Lawrence, T.;
Bebien, M.; Liu, G. Y.; Nizet, V.; Karin, M. Nature 2005, 434, 1138.
15. (a) Serine/threonine kinase panel: MKK1, MAPK2/ERK2, JNK/SAPK1c, SAPK2a/
p38, SAPK2b/p38b2, SAPK3/p38g, SAPK4/p38d, MAPKAP-K1a, MAPKAP-K2,
MSK1, PRAK, PKA, PKCa, PDK1, PKBDPH, SGK, S6K1, GSK3b, ROCK-II, AMPK,
CHK1, CK2, PHOS.KINASE, Lck, CSK, CDK2/cyclin A, CK1, DYRK1a, PP2a.; (b)
Tyrosine kinase panel: Btk, Eck, EGFR, FGFR3, Hek, HGFR, IGF1R, IR, Itk, Lyn,
PDGFRa, Syk, TrkA, VEGFR1.