Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design

Article abstract of DOI:10.1016/j.bmcl.2008.12.028

Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inf

Full text of DOI:10.1016/j.bmcl.2008.12.028

Bioorganic & Medicinal Chemistry Letters 19 (2009) 773–777
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK)
through structure-based drug design
a
a
a
a
a
Brian N. Cook a, , Jörg Bentzien , Andre White , Peter A. Nemoto , Ji Wang , Chuk C. Man ,
Fariba Soleymanzadeh a, Hnin Hnin Khine b, Mohammed A. Kashem c, Stanley Z. Kugler Jr. c, John P. Wolak c,
Gregory P. Roth a, , Stéphane De Lombaert a, Steven S. Pullen b, Hidenori Takahashi a
*
a Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA
b Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA
c Biomolecular Screening, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell
activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could
provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors
through structure-based design where high-resolution crystal structural information was used to opti-
mize interactions within the kinase specificity pocket of the enzyme to improve both potency and
selectivity.
Received 21 October 2008
Revised 3 December 2008
Accepted 4 December 2008
Available online 10 December 2008
Keywords:
Kinase
Ó 2009 Elsevier Ltd. All rights reserved.
Structure-based drug design
ITK
Tec kinase
SAR
Inhibitor
Benzimidazole
Interleukin-2 inducible T-cell kinase (ITK) is a member of the
Tec family of non-receptor tyrosine kinases which has been found
to play an important role in T-cell activation and proliferation.1 ITK
is expressed primarily in T-cells, NK cells, and mast cells. Upon
stimulation of the T-cell receptor (TCR), ITK is activated and serves
to amplify the TCR signaling cascade.2 Murine CD4+ T-cells lacking
Itk showed reduced IL-2, IL-4, IL-5, and IL-13 production upon
T-cell receptor stimulation.3–5 ITK therefore represents a novel
potential target for anti-inflammatory therapy in a variety of indi-
cations such as psoriasis and allergic asthma.6
tyrosine kinase (IRK), an enzyme with close structural homology
to ITK. Unsubstituted analogs such as compound 1 displayed poor
selectivity with an IRK IC50 of 560 nM. A series of substituted phe-
nyl analogs showed good selectivity and improved potency, yet
still displayed modest cellular potency.8 Therefore, we focused
our optimization effort on increasing the molecular and cellular
potency of the lead series, while concomitantly maintaining or
improving its selectivity over IRK and other related kinases.
We have recently reported on the identification of a structurally
new lead series7 and initial optimization studies8 that culminated
in a number of acylated 2-aminobenzimidazoles, represented here
by compound 1 shown in Figure 1. Compound 1 displayed good
potency in a DELFIA-based molecular assay7 (IC50 = 180 nM) and
moderate cellular potency (IC50 = 2.3 lM), as measured in a stably
transfected, Itk-expressing DT40 cell line assay.7 This series of
compounds was tested for selectivity against insulin receptor
* Corresponding author. Tel.:+1 203 798 5730.
E-mail address: brian.cook@boehringer-ingelheim.com (B.N. Cook).
Present address: Burnham Institute for Medical Research at Lake Nona, Orlando,
FL 32819, USA.
Figure 1. The structure and binding mode of 1 in ITK.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.028

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B. N. Cook et al. / Bioorg. Med. Chem. Lett. 19 (2009) 773–777
Scheme 1. General method for synthesis of 2-aminobenzimidazoles. Reagents and conditions: (a) benzoyl chloride, pyridine, CH2Cl2, 0 °C–rt; (b) CH3I, NaH, THF rt, 24 h;
(c) 3-aminopropanamide, DIEA, CH3CN, 50 °C, 24 h; (d) Pd/C, H2, CH3OH; (e) BrCN, EtOH; rt, 24 h; (f) benzoic acid, EDCI, DIEA, DMF, rt, 24 h.
Structure-based drug design offered an appealing opportunity
towards that end. Indeed, crystallographic information revealed a
number of new potential interactions that could be gained.9 Of
particular interest is a vacant kinase specificity pocket (KSP) adja-
cent to the ATP binding site. This pocket is analogous to other
reported KSPs,10 which have been successfully exploited to yield a
substantial increase in both potency and selectivity with other
kinase inhibitors.11 Access to this pocket is restricted by Phe435
which serves as a gatekeeper residue.9 Previous reports suggest that
gatekeeper residue interactions are a route to increase both potency
and selectivity, as this residue often varies between disparate
kinases.12 Within the pocket, there exists a variety of functional
groups that could be exploited to increase potency, such as the con-
formationally flexible Lys391, Glu406 (which makes up part of the
distal surface of the pocket), and DGF motif loop at the bottom por-
tion of the pocket (Asp500, Gly501, Phe502). This is in stark contrast
to the lipophilic nature of the majority of KSPs described in the liter-
ature.10 Based on the available crystallographic information, it
appeared that placement of the appropriate functionality within
the KSP should significantly increase binding potency.
The general synthetic route is shown in Scheme 1. The commer-
cially available 4-methyl-3-nitro-aniline (2) was acylated with
benzoyl chloride and then N-alkylated through treatment with
NaH and methyl iodide. Amine containing side-chains were intro-
duced through SNAr displacement of the activated aromatic fluo-
ride 3, and the nitro group was then reduced quantitatively to
yield diamino compound 4. Dianiline 4 was treated with cyanogen
bromide to provide the 2-aminobenzimidazole 5, which was acyl-
ated using standard conditions to provide the desired ITK inhibi-
tors. The various carboxylic acids used were synthesized through
standard methods.
Our initial attempt to improve the potency of compound 1 was
focused on substitution of the phenyl ring. Of particular impor-
tance was substitution at the 4-position, as modeling suggested
it would most likely point towards the Phe435 gatekeeper and
the unoccupied KSP.
Small substituents at the 4-position increased both potency and
selectivity, as observed previously8 and in agreement with the
molecular modeling prediction. Since the corresponding gate-
keeper residue in IRK is a Met residue, it is hypothesized that the
increase in selectivity over IRK results from unfavorable steric
interactions at the 4-position. Interestingly, large groups, such as
a phenyl ring, are not tolerated at the 4-position (compound 10),
again likely due to the position of the gatekeeper residue. However,
the potencies of compounds 11 and 12 suggest that substitution at
the 3-position may avoid the unfavorable Phe435 interaction,
thereby providing a route around the gatekeeper residue and into
the KSP (Table 1).
Based on these results, a number of other 3-substituted phenyl
analogues were designed and synthesized. Unfortunately, none of
those compounds showed a significant increase in potency (data
not shown). Therefore, a series of heterocyclic derivatives were con-
sidered to find alternatives for the phenyl group of 1. We reasoned
that 5-membered ring heterocycles could present a unique opportu-
nity to achieve bonding angles similar to biphenyl analogue 11,
while offering access to the KSP, around the gatekeeper residue.
The 2-substituted thiophene analog had already been shown during
the hit-to-lead phase to be a potent ITK inhibitor.7 Other simple
unsubstituted heterocycle analogues were explored first to deter-
mine if they would serve as effective phenyl replacements (Table 2).
The acylated 2-aminobenzimidazole lead series displays a
somewhat unique binding motif to the hinge region of ITK. The
double bond of the benzimidazole core exists as the exo-tautomer
as supported by both NMR NOE studies in solution and X-ray crys-
tallography of the molecule in complex with the ITK protein.7–9
Two hydrogen bonds are observed between Met438 in the hinge
region of the peptide backbone and the benzimidazole ring N–H
as well as the acyl carbonyl oxygen. The tautomerization of the
benzimidazole ring is critical for high affinity ITK binding for this
series, as compounds lacking either of the H-bonding components
were found to show no activity against ITK.7,9 Critical to establish-
ing the proper H-bonding interactions through the exo-tautomer is
the aryl substituent on the right hand side of the molecule.
Replacement of this aryl group with a simple alkyl or cycloalkyl
group provided compounds that do not exist as the requisite tau-
tomers (as observed by NOE) and, therefore, lack any measurable
ITK inhibitory activity.7
Among several approaches devised to access the vacant KSP,13
this work describes a lead optimization strategy specifically aimed
at achieving this goal via a biaryl binding motif.

B. N. Cook et al. / Bioorg. Med. Chem. Lett. 19 (2009) 773–777
775
Table 3
Table 1
RHS 5-thienyl substitution SAR
RHS aryl SAR
Compound
R
ITK IC50
(
lM)
IRK IC50
(
lM)
DT40 IC50 (lM)
Compound
Ar
ITK IC50
(lM)
IRK IC50
(l
M)
DT40 IC50 (lM)
14
22
23
24
25
26
27
28
29
30
31
32
33
34
H
Cl
Br
CN
0.058
0.014
0.015
0.015
0.002
0.014
0.020
0.055
0.14
0.035
0.039
0.019
0.005
0.002
0.15
0.38
0.63
3.8
2.7
1
6
7
8
9
10
11
12
13
Phenyl
0.18
0.018
0.017
0.17
0.026
>10
1.0
2.5
0.095
0.56
5.6
2.3
1.3
0.52
0.10
0.15
0.02
0.39
0.57
0.15
0.47
1.2
0.82
0.65
0.04
0.51
4-Cl-phenyl
4-CN-phenyl
4-OMe-phenyl
4-Br-phenyl
4-Biphenyl
3-Biphenyl
1-Naphthyl
2-Naphthyl
>6.0
>6.0
>6.0
>6.0
>6.0
5.8
0.33
>5.0
0.73
>5.0
0.09
>5.0
0.54
CHO
COCH3
COCH(CH3)2
COPh
OPh
OBn
Ph
2-Pyr
3-Pyr
4-Pyr
0.051
>6.0
>6.0
>6.0
>6.0
>6.0
>6.0
>6.0
>6.0
>6.0
>6.0
Table 2
RHS aryl replacement SAR
diate. To a lesser extent, the ketone containing compounds 26–28
may also interact with the Lys391 residue. These compounds show
improved selectivity against IRK, however, likely due to the distinct
steric requirements of the gatekeeper residues in the different
active sites.
Aryl substitution (examples 31–34) was tolerated at the 5-posi-
tion, confirming that the 5-position of the thiophene offered a ben-
eficial presentation of functionality which avoided the Phe435
gatekeeper residue. Of particular significance was the dramatic
increase in molecular and cellular potency of the 3- and 4-pyridine
functionalized compounds. Introduction of the 2-pyridyl motif (32)
did not result in a substantial increase in potency as compared to
the phenyl analogue 31. However, both the 3- and 4-pyridyl ana-
logues 33 and 34 (respectively) showed much improved molecular
potency, with similar gains observed in the cellular assay for 33. In
addition, these compounds displayed very good selectivity against
IRK.
Compound
Ar
ITK IC50
(lM)
IRK IC50
(lM)
DT40 IC50 (lM)
1
14
15
16
17
18
19
20
21
Phenyl
0.18
0.058
0.057
0.34
0.13
0.45
0.17
0.18
0.10
0.56
0.15
0.24
6.1
2.3
2.7
1.6
>5.0
>5.0
>5.0
>5.0
>5.0
>5.0
2-Thiophene
3-Thiophene
4-Thiazole
5-Thiazole
2-Oxazole
4-Oxazole
5-Oxazole
5-Isoxazole
1.6
>6.0
>6.0
>6.0
>6.0
A co-crystal structure of compound 32 with ITK was obtained,
providing insights about the interactions within the KSP. As shown
in Figure 2, the 2-pyridyl moiety of 32 may benefit from a hydro-
As observed previously,7 the thiophene group served as a good
replacement of the phenyl group, resulting in a compound of
increased potency. The other heterocycles tested showed a rela-
tively flat SAR in terms of ITK potency, although increased IRK
selectivity was usually observed. We hypothesized that this could
again result from unfavorable interactions (perhaps electrostatic in
nature) with the IRK Met gatekeeper residue. Since substitution of
the thiophene would allow for presentation of other groups at
angles distinct from the corresponding phenyl analogs, the 2,5-
disubstituted thiophene was chosen as a scaffold for further opti-
mization as shown in Table 3.
Substitution at the 5-position of the thiophene ring was found
to increase potency dramatically. Simple halogen substitution, as
in 22 and 23, increased molecular potency 4-fold, with similar
gains observed in cellular potency. Cyano substitution at the 5-po-
sition also enhanced potency, while providing a 250-fold selectiv-
ity for ITK over IRK (see compound 24). Appending a 5-formyl
group provided the highly potent compound 25, likely though
formation of a covalent intermediate with Lys391. In follow-up
experiments, incubation of the enzyme with compound 25 in the
presence of a reducing agent showed formation of the irreversible
Lys391 adduct, supporting the formation of a Schiff’s base interme-
phobic
p-stacking interaction with the gatekeeper Phe435, which
is absent in the IRK active site. In addition, the pyridine ring points
directly into the vacant selectivity pocket. From the structure, the
2-pyridine does not appear to pick up any additional interactions.
However, compounds 33 and 34 may be able to engage in hydro-
gen bonding interactions with either Lys391 or Asp500, resulting
in the increased potencies observed.
Based on these results, the thiophene biaryl inhibitors were fur-
ther modified through the introduction of pendant heterocyclic
replacements of the pyridine motif of 32–34 (Table 4). The various
oxazole analogues showed good potency when assayed against
ITK, with the 5-oxazole being the most potent. This compound
overlaps nicely with the 3-pyridyl analogue 33 which was previ-
ously observed to impart high potency. The 2- and 4-oxazoles dis-
played reduced activity, similar to 2-pyridyl analogue 32, again
suggesting that opportunities for H-bonding interactions exist
deep within the KSP. All other nitrogen containing aromatic het-
erocycles were potent ITK inhibitors, while saturated analogues
43–46 were weaker. This loss of potency was attributed to a lack
of a
p-stacking interaction with Phe435, or unfavorable electro-

776
B. N. Cook et al. / Bioorg. Med. Chem. Lett. 19 (2009) 773–777
Figure 2. The X-ray crystal structure of 32 and interactions in the KSP of ITK.
static repulsion between Lys391 and the protonated basic amine
(or oxygen heteroatom) in the saturated ring system.
Interestingly, pyrazole analogue 41 was the most potent com-
pound tested in the cellular assay, with an IC50 of 2 nM. It was
25-fold more potent than 5-oxazole analogue 37) even though
they displayed similar molecular potency under the assay condi-
tions. Based on the conditions used for the molecular assay, the
predicted assay range does not extend below 2 nM. Therefore,
we developed an assay with a higher concentration of ATP to
extend the dynamic range of the assay, thereby allowing for
the direct comparison of the most potent of inhibitors. Addi-
tional analogues containing the pyrazole and 5-oxazole moieties
were synthesized with various groups appended from the 1-po-
sition of the benzimidazole to improve physicochemical proper-
ties of the molecules. When these analogues were tested in the
higher ATP concentration assay, the pyrazole analogues were
Figure 3. The molecular modelling structure and binding mode of pyrazole
compound 41 in the KSP. Two possible H-bond interactions are observed to K391
and D500.
found to be consistently 10-fold more potent than the corre-
sponding oxazole analogues. This finding supports the cellular
potency increase observed in the case of pyrazole analogue 41.
Molecular modeling suggests that the pyrazole is able to form
two distinct hydrogen bonds within the KSP: one with Lys391
and the other with Asp500. In addition, the T-shaped orientation
of the heterocycle and the aryl ring of Phe435 can provide a
favorable interaction (Fig. 3 below). In contrast, the oxazole ana-
logue occupies a similar space, but only benefits from a single
hydrogen bond interaction with Lys391.
Both the oxazole and pyrazole derivatives showed greater than
1000-fold selectivity over IRK. This is in stark contrast to lead com-
pounds 1 and 14, which each showed approximately 3-fold selec-
tivity. In addition, the cellular potency of the biaryl compounds
was increased more than 1000-fold over the unsubstituted thio-
phene inhibitor 14.
Table 4
RHS 5-thienyl substitution SAR
In summary, a series of biaryl thiophene-containing ITK inhib-
itors was identified. These compounds were designed to avoid
the gatekeeper Phe residue and occupy the vacant KSP of ITK
to increase potency and selectivity against IRK. Molecular model-
ing as well as X-ray crystallography guided molecule design and
led to ITK inhibitors that showed
increase in molecular potency and
a
greater than 100-fold
coincident 1000-fold
Compound
R
ITK IC50
M)
IRK IC50
M)
DT40 IC50
M)
(
l
(
l
(l
a
increase in cellular potency. In addition, selectivity for ITK inhi-
bition over IRK was increased from 3-fold to greater than 1000-
fold. Notably, compound 41 is the most potent ITK inhibitor
reported to date. Further details regarding the in vivo efficacy
of these biaryl-containing ITK inhibitors will be presented in
forthcoming publications.
35
36
37
38
39
40
2-Oxazole
4-Oxazole
5-Oxazole
2-Me-5-oxazole
2-Thiazole
2-Amino-4-
Thiazole
4-Pyrazole
2-Pyrazine
Pyrrolidine
0.008
0.014
0.002
0.006
0.011
0.010
>6.0
>6.0
5.2
2.4
>6.0
>6.0
0.10
0.74
0.05
0.06
0.19
1.3
41
42
43
44
45
46
47
48
49
50
51
0.002
0.013
0.081
0.38
2.0
>6.0
>6.0
>6.0
>6.0
>6.0
>6.0
>6.0
>6.0
>6.0
>6.0
0.002
0.73
1.8
>3.2
>3.2
>3.2
References and notes
Piperidine
Piperazine
0.15
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