Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.11.013

A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described. These compounds were used as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt/TCF4/β-catenin-driven transcription or viability. The findings suggest that the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function, such as its putative role in stabilizing the TCF4/β-catenin transcriptional complex.

Full text of DOI:10.1016/j.bmcl.2012.11.013

Bioorganic & Medicinal Chemistry Letters 23 (2013) 569–573
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors
⇑
Koc-Kan Ho , K. Mark Parnell, Yi Yuan, Yong Xu, Steven G. Kultgen, Steven Hamblin,
Thomas F. Hendrickson, Bai Luo, Jason M. Foulks, Michael V. McCullar, Steven B. Kanner
Astex Pharmaceuticals, Inc., 2401 South Foothill Drive, Salt Lake City, UT 84109, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 June 2012
Revised 29 October 2012
Accepted 7 November 2012
Available online 16 November 2012
A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective
inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described. These compounds were used
as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated
colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has
minimal effects on either Wnt/TCF4/b-catenin-driven transcription or viability. The findings suggest that
the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function,
such as its putative role in stabilizing the TCF4/b-catenin transcriptional complex.
Keywords:
TNIK
Wnt signaling
b-catenin
Ó 2012 Elsevier Ltd. All rights reserved.
TCF4
Phenylaminopyridine
The Wnt signaling pathway plays a major role in colorectal can-
cer. In nearly 90% of colorectal cancers, activating mutations in
Wnt pathway components lead to increased transcription through
the TCF4/b-catenin transcriptional complex, resulting in increased
cell proliferation.1–3 Recent reports have identified Traf2- and
Nck-interacting kinase (TNIK) as critical for Wnt signaling and pro-
liferation of colon cancer cells,4,5 and small molecule inhibitors
were reported.6 Evidence suggests that in response to Wnt signal-
ing, TNIK localizes to the nucleus and phosphorylates TCF4 on
Ser154, and that the kinase activity of TNIK is necessary for TCF4
transcriptional activity and maintenance of colorectal cancer
growth.5 These findings suggest that small molecule TNIK inhibi-
tors may be useful therapeutic agents in colorectal cancers with
aberrant Wnt signaling.
A biochemical assay was developed to screen for TNIK inhibi-
tors utilizing the Promega ADP Glo system, in which ADP formed
during the kinase reaction produces a proportional luminescent
signal.7 Using this assay, a small in-house collection of compounds
(ꢀ500) with known or predicted kinase inhibitory activity were
screened. Among the screen hits was compound 1 which inhibited
TNIK biochemical activity with an IC50 = 65 nM (Table 1).
Compound 1 also inhibited the binding of ATP to TNIK in an
orthogonal ATP competition assay (Kd = 86 nM, KdELECT, KINOMEs-
can, DiscoveRx, CA, USA).
Reaction Biology, PA, USA). More than half of the kinases in the pa-
nel were inhibited by at least 50% at 1 M concentration of 1
(S(50) = 56%, Table 2), indicating poor selectivity. This was not a
l
surprising result given that the phenylaminopyrimidine moiety
in
1 is a common motif found in many kinase inhibitors.
Consequently, a tool compound with significant improvement in
general kinase selectivity was needed in order to interrogate the
target. One of the approaches to improve kinase selectivity was
to alter the nature of the hinge binding domain, therefore the ami-
nopyrimidine moiety in compound 1 (Table 1). Replacing the
pyrimidine ring in 1 with a pyridine yielded a structurally related
compound 2, in which the calculated pKa (ACD/pKa, Advanced
Chemistry Development, Inc., Ontario, Canada) of the pyridine
nitrogen is 5.08 as compared with 0.18 for the corresponding
pyrimidine nitrogen. It was postulated that altering the pKa could
change the property of the hinge binding interactions and could
change the selectivity profile of a compound. Although compound
2
was less potent against TNIK (IC50 = 290 nM, ADP Glo;
Kd = 220 nM, KdELECT), it appeared to be more selective than 1
against a small number of in-house kinase targets (data not
shown). This observation led us to explore 4-phenyl-2-phenylami-
nopyridines as a potential scaffold for TNIK inhibitors. Replace-
ment of the 3-cyanomethyl group in 2 with a 3-cyano (3)
increased the inhibition against TNIK to IC50 of 6 nM. Compound
3 was over 40-fold more potent than the parent compound 2,
and 10-fold more potent than screening hit 1. Kinase selectivity
analysis of 3 showed that only 6 of the 118 kinases in the oncoKP
To determine the kinase selectivity of 1, the compound was
screened against a panel of 118 oncogenic kinases (oncoKP,
panel were inhibited by 50% or more at 1
(S(50) = 5.1, Table 2). In addition, it was found that TNIK was the
lM concentration of 3
⇑
Corresponding author. Tel.: +1 732 896 7363.
E-mail address: kanho99@yahoo.com (K.-K. Ho).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.013

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K.-K. Ho et al. / Bioorg. Med. Chem. Lett. 23 (2013) 569–573
Table 1
Properties of initial TNIK hits
CN
CN
N
N
N
N
O
N
N
H
O
N
N
H
1a
2
3
1a
2
3
Molecular weight
TNIK IC50 (nM)
449.0
65
Not determined
413.5
290
94
399.5
6
78
Solubility (
l
M)b
Caco-2 Papp(A–B) (nm/sec)
Caco-2 Papp(B–A) (nm/sec)
Caco-2 Papp(B–A)/Papp(A–B)
80
77
0.96
205
191
0.93
160
142
0.89
a
Highlighted area represents the hinge binding domain.
Solubility was determine at100 mM phosphate buffer, pH 7.4.
b
most potently inhibited kinase, with inhibition of >99% at 1
concentration. The only other kinase with less than 95% inhibition
at 1 M concentration of 3 was MAP4K4 (98% inhibition at 1
concentration), which is 90% identical to TNIK in its kinase domain
sequence.8 It was concluded that the 4-(3-cyanophenyl)-pyridine
core of 3 interacts with the TNIK in high selectivity.
l
M
using a recently published TNIK crystal structure (PDB entry 2X7F).
Figure 1 shows energy minimized poses for 1 and 3. Both com-
pounds share a common binding motif, with classic ‘hinge binding’
hydrogen bonds between the aminopyrimidine (1) or aminopyri-
dine (3) moieties and the hinge region backbone amide NH of
Phe107 and the carbonyl O of Cys108. The protonated methylpi-
perazine group is predicted to interact through a salt bridge with
the carboxy group of Asp115. The principal difference in the
l
lM
To gain insight on the compound’s binding poses to the TNIK ac-
tive site, modeling studies were performed on compounds 1 and 3
Table 2
Activity of compounds 1 and 3 against a panel of oncogenic kinases
1
3
Selectivity score S(50)a
>95% Inhibition at 1
56%
5.1%
TNIK, MAP4K4
l
M
JAK2, VEGFR3, JAK3, RET, FGFR1, FLT3, IKK
FGFR3, TRKC
e, VEGFR2, p70S6K, Aurora A, VEGFR1, ROS, FGFR2,
95 to >80% Inhibition at 1
lM
ABL2, Aurora B, CDK4/cyclin D1, FMS, MEK1, BRK, CDK6/cyclin D1, CHK1, FER, CHK2, YES, PDGFRb,
LCK, c-SRC, ABL1, NEK1, HIPK3, MEK2, HIPK4, TRKA, Syk, JAK1, AXL, LYN, FES, IGF1R, PDGFR , MUSK,
Aurora C, DAPK1, CK2 , c-KIT, TRKB
FAK, PAK4, EPHB1, FGR, CDK9/cyclin T1, FYN, PYK2, PKCd, EPHA1, CDK2/cyclin A, EPHA7, HIPK1,
PKC , PKCh, MST4, CDK1/cyclin B, HCK, TIE2
IKK
e
a
a
80–50% Activity at 1
l
M
FLT3, CDK6/cyclin D1,
FMS, CHK1
e
a
S(50) indicates the percentage of kinases in panel (118 total) inhibited by >50% at 1 lM concentration.
Figure 1. Compounds 1 (brown carbons) and 3 (green carbons) in the ATP binding pocket. The surface was generated from the TNIK protein with several of the flap residues
removed for clarity. Hinge region, sugar binding region, and catalytic residues are indicated. The yellow mesh is the molecular surface for compound 3. The modeling study
was performed using a TNIK crystal structure (PDB entry 2X7F). Compounds 1 and 3 were docked to the protein and energy minimized using GLIDE and MacroModel
(Schrödinger, NY, USA), respectively.

K.-K. Ho et al. / Bioorg. Med. Chem. Lett. 23 (2013) 569–573
571
Table 3
SAR for 4-phenyl-2-phenylaminopyridine based TNIK inhibitors
R1
A
R2
R4
R3
N
N
H
B
Compound
R1
R2
R3
R4
TNIK IC50 (nM)
hERGa IC50
1.3
(lM)
N
N
N
N
N
3
3-CN
3-CN
3-CN
3-Cl
H
MeO
H
6
N
N
N
N
N
N
N
N
N
N
N
N
4
6-MeO
6-MeO
6-MeO
H
5
5
MeO
MeO
MeO
H
3
6
4
7
3-CN
3-CN
3-CN
4-CN
3-Cl
55
11
8
7.7
4.7
20
O
O
O
O
O
O
O
O
8
6-MeO
6-MeO
H
9
MeO
MeO
MeO
MeO
MeO
MeO
F
10
11
12
13
14
15
>1,000
41
118
275
63
11
6-MeO
6-MeO
6-MeO
5-MeO
6-MeO
3-F
3-CF3
3-CN
3-CN
N
O
N
16
3-Cl
6-MeO
H
20
a
hERG IC50 was determined by a FastPatch assay (WuXi PharmaTech, Shanghai, PRC).
R1
R1
R2
R2
R'O
R2
I
H2N
R4
B
R1
R'O
R3
R4
R3
N
Cl
a
b
N
Cl
N
N
H
17
R' = H
or
R',R' =
18
Compound 3, 4, 6, 7, 9, 10 and 16
Scheme 1. Reagents and conditions: (a) Pd(PPh3)4, Na2CO3, dioxane/water, 100 °C, 4 h. (b) HCl, iPrOH, microwave 170 °C, 12 h.
binding modes of 1 and 3 is in the substituted phenyl group, which
in both cases is oriented toward the catalytic residues. In com-
pound 1, the nitrogen of the cyanomethyl group accepts a hydro-
gen bond from the catalytic Lys54. In compound 3, there are no
predicted hydrogen bonds, as the cyano group is directly attached
to the phenyl ring and is therefore much less flexible. Instead, the
cyano group is nestled in a mostly hydrophobic pocket between
residues Leu103, Leu73 and Met105, which is an energetically
favorable interaction according to our model. The position of the
cyano group allows both the pyridine ring and the phenyl ring of
compound 3 to interact more closely with residues Met105,
Val170 and Ala83, picking up additional hydrophobic interactions.
Compounds 1–3 were tested in a Caco-2 assay to determine cell
permeability. Compounds with a pyridine core (2 and 3), demon-
strated Caco-2 permeability coefficients at 160–205 nm/s that
were roughly 2-fold greater than the pyrimidine 1, with no evi-
dence of efflux (Table 1). Therefore, cell permeability is unlikely
the limiting factor for triggering a cellular response for the series.
Given that 3 was potent against TNIK, highly selective, and
cell permeable, medicinal chemistry efforts were focused on

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K.-K. Ho et al. / Bioorg. Med. Chem. Lett. 23 (2013) 569–573
R1
R2
R2
R'O
H2N
R4
I
I
B
R4
R1
R4
R3
R'O
R3
N
F
N
N
H
R3
b
a
N
N
H
R' = H
or
R',R' =
19
20
Compound 5, 8, 11, 12, 13,
14 and 15
Scheme 2. Reagents and conditions: (a) HCl, dioxane/water 102 °C, 20 h. (b) Pd(dppf)Cl2, K2CO3, dioxane/water 80 °C, 16 h.
Table 4
siRNA: Control siRNA1 siRNA2 siRNA3
Comparison of biochemical inhibition of TNIK and cell-based inhibition of Wnt-driven
b-lactamase for a set of 4-phenyl-2-phenylaminopyridines
TNIK
Compound
TNIK IC50
(nM)
b-lactamase IC50
(nM)
b-lactamase IC50/TNIK
IC50
3
4
6
8
9
15
1
6
5
4
11
8
27,000
>30,000
7900
26,000
6300
3100
350
4500
>6000
2000
2400
790
11
65
280
5.4
*
*
*
Staurosporine 1.4
39
28
eliminating the hERG liability associated with the highly basic
methylpiperidinyl moiety in compound 3. Through patch clamp
analysis, it was determined that 3 inhibited hERG with an IC50 of
siRNA: Control siRNA1 siRNA2 siRNA3
1.3 lM (Table 3). However, given the potential of hERG-based
Figure 2. RNAi knockdown of TNIK in HCT-116 cells correlates with a decrease in
viability. Top panel indicates TNIK levels, measured by Western blot with anti-TNIK
antibody, following transient transfection with siRNAs 1 through 3 targeting TNIK,
as well as scrambled siRNA control. Bottom panel indicates% viability of siRNA
transfected HCT-116 cells. Control siRNA was purchased from Thermo Fisher
Scientific (Non-targeting siRNA D-001810-01-05). TNIK siRNA was purchased from
Qiagen (Cat # SI02225503, SI03649856, and SI05187980). ⁄The P-value for each
siRNA versus control was <0.01.
clinical cardiac toxicity,9 our goal was to reduce the potency of
the series against the hERG channel.
A series of analogs (Table 3) were prepared by a two step
synthesis utilizing a Suzuki coupling and a SNAr reaction. Using
2-chloro-4-iodopyridine 17 as starting material, a boronic acid or
ester was selectively coupled to the 4 position of the pyridine
(Scheme 1). The resulting chloropyridine 18 was then reacted with
an aniline to yield the desired analogs. The reaction sequence can
be reversed when a starting material of 2-fluoro-4-iodopyridine
19 was used (Scheme 2).
Having developed a series of potent and selective TNIK inhibi-
tors, the next step was to explore the importance of TNIK kinase
activity in Wnt-activated colorectal cancer cells. The hypothesis,
based on previous studies was that pharmacological inhibition of
TNIK activity would block TCF4/b-catenin-dependent transcrip-
tion.4,5 To test this hypothesis, a Wnt-activated colorectal cancer
cell line (HCT-116) with a stably expressed TCF4/b-catenin-response
element upstream of a b-lactamase reporter gene (CellSensorÒ,
Invitrogen)10 was used. In short, Wnt signaling through TCF4/
b-catenin transcription results in constitutive expression of b-lac-
tamase, and the activity of b-lactamase is measured by conversion
of its substrate into a product with a shifted fluorescent signal. Sev-
eral TNIK inhibitors were tested in this assay and the results are
summarized in Table 4. The IC50 values for the compounds tested
Replacement of the 4-methylpiperazine of 3 with a non-basic
morpholine as in compound 7 decreased activity against both
hERG (IC50 = 8 lM) and TNIK (IC50 = 55 nM) (Table 3). Substitution
of a 6-methoxy in the R2 (compound 9) increased TNIK activity
(IC50 = 8 nM) while only modestly increasing hERG activity
(IC50 = 4.7
activity was achieved by replacing the cyano group in R1 with a
chloro moiety yielding compound 11 with hERG IC50 of 20 M.
lM) as compared with 7. Further reduction in hERG
l
Initial SAR suggested that a methoxy substitution either in the
6-position of R2 or in R3 does not affect the potency when the R4
is a methylpiperidine. The methylpiperidine analogs 3, 4, 5 and 6
show similar potency. However, a more significant improvement
in potency is observed for the di-methoxy analog 9 as compared
with the mono-methoxy analog 7 when R4 is a morpholine. For
Ring A, it is observed that a 3-cyano is preferred over 4-cyano
group in R1 since compound 10 is devoid of TNIK activity. The 3-
cyano in the A ring can also be replaced with a 3-chloro group (11),
but inferior activity was observed for a 3-fluoro (12) or a trifluoro-
methyl (13) compounds. Comparing the activity of compounds 9
and 14, it is evident that 6-methoxy is preferred over the 5-meth-
oxy moiety. In addition, compounds 15 and 16 with modifications
in Ring B were prepared to expand the chemical diversity, so multi-
ple chemotypes could be evaluated for cellular activity.
in these cells ranged from 3.1 to >30 lM, more than 280-fold high-
er than the biochemical TNIK IC50 values, and much higher than ex-
pected if TNIK kinase activity were essential for TCF4/b-catenin
transcription. ICG-001, a compound that prevents the interaction
of b-catenin with the co-activator CBP and thus inhibits TCF4/b-
catenin-dependent transcription, was included as a positive con-
trol.11 We observed an IC50 of 1.3
the published IC50 of 1.3
l
M for ICG-001, identical to
l
M,11 indicating that the assay was in-
deed responsive to signaling through the TCF4/b-catenin pathway.
We found that analog 1, which was observed to be a non-selective
kinase inhibitor, inhibited the b-lactamase reporter assay with an

K.-K. Ho et al. / Bioorg. Med. Chem. Lett. 23 (2013) 569–573
573
Table 5
scaffolding interactions may play an important role in its function
in Wnt-activated colorectal cancer cells.
Comparison of biochemical inhibition of TNIK and viability inhibition for Wnt-active
and Wnt-inactive cell lines
In addition to the proposed role for TNIK in Wnt signaling, TNIK
has been implicated in actin cytoskeleton regulation,8 as a media-
tor of Ras family member Rep2, which regulates cell proliferation,
differentiation, and cytoskeletal rearrangement.13 Recent evidence
has also identified TNIK as a schizophrenia susceptibility gene,
influencing neural circuit synchrony.14 The above-described TNIK
inhibitors may be useful tools to interrogate these aspects of TNIK
biology.
Compound
TNIK IC50 (nM)
Viability IC50 (nM)
Wnt-active Wnt-inactive
HCT-116
DLD1
HEK-293
HeLa
9
15
16
8
11
20
2300
260
1700
5800
330
1100
105
43
59
6800
1200
3700
The compounds described here also inhibit the closely-related
MAP4K4 kinase (Table 2),8 which has been implicated in hepatoma
carcinoma growth15 and invasion,16 as well as a general factor pro-
moting tumor cell motility.17,18 MAP4K4 expression is correlated
with metastasis and inversely correlated with survival in colorectal
cancer,19 and is associated with poor prognosis in pancreatic ductal
adenocarcinoma.20 Thus, these inhibitors may have utility to better
understand the function of MAP4K4 in cancer.
IC50 of 350 nM. Similarly, staurosporine demonstrated an IC50 of
39 nM in the same assay. These results suggested that Wnt signal-
ing through TCF4/b-catenin is sensitive to kinase signaling, but the
kinase activity of TNIK is nonessential for that function.
The viability of colorectal cells with activated Wnt signaling has
been shown to be TNIK-dependent through RNAi-based knock-
down experiments,4,5 though the effect on viability was not shown
to be dependent upon TNIK kinase activity. In our studies, RNAi-
based knockdown of TNIK resulted in a corresponding decrease
in viability in HCT-116 cells (Fig. 2), but not in Wnt-inactive HeLa
cells (data not shown). In contrast, the viability effects observed
with TNIK inhibitors were not specific to Wnt-active colorectal
cancer cells (Table 5). Indeed, the compounds appeared most toxic
to Wnt-inactive HEK-293 cells. The data suggests that viability ef-
fects by the TNIK inhibitors (such as 15) were likely due to effects
on pathways other than the Wnt signaling pathway.
References and notes
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In conclusion, a series of potent and selective small molecule
TNIK inhibitors were identified. Starting with 1, a relatively pro-
miscuous compound, potency and selectivity were subsequently
built in with few modifications. These tool compounds were used
for target validation. Here, pharmacological inhibition of TNIK
did not inhibit Wnt signaling through TCF4/b-catenin-mediated
transcription, whereas less selective kinase inhibitors, such as
compound 1 and staurosporine, inhibited Wnt signaling (Table
4). It remains unlikely that this result was due to compound imper-
meability, as Caco-2 data indicates that pyridine-containing com-
pounds such as 3 were cell permeable (Table 1). The more likely
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scription, a Wnt pathway specific viability effect was not observed
with the TNIK inhibitors (Table 5). In contrast, a viability effect in
Wnt-activated cells upon siRNA knockdown of TNIK was observed
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