Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease

Article abstract of DOI:10.1016/j.bmcl.2018.09.022

The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.

Full text of DOI:10.1016/j.bmcl.2018.09.022

Accepted Manuscript
Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the
topical treatment of inflammatory skin disease
Michael D. Barker, John Liddle, Francis L. Atkinson, David Matthew Wilson,
Marion C. Dickson, Cesar Ramirez-Molina, Huw Lewis, Rob P. Davis, Donald
O. Somers, Margarete Neu, Emma Jones, Robert Watson
PII:
S0960-894X(18)30753-4
https://doi.org/10.1016/j.bmcl.2018.09.022
BMCL 26043
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 August 2018
14 September 2018
17 September 2018
Please cite this article as: Barker, M.D., Liddle, J., Atkinson, F.L., Wilson, D.M., Dickson, M.C., Ramirez-Molina,
C., Lewis, H., Davis, R.P., Somers, D.O., Neu, M., Jones, E., Watson, R., Discovery of potent and selective Spleen
Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease, Bioorganic & Medicinal
Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.09.022
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Bioorganic & Medicinal Chemistry Letters
Discovery of potent and selective Spleen Tyrosine Kinase inhibitors
for the topical treatment of inflammatory skin disease
Michael D. Barker*, John Liddle, Francis L. Atkinsona, David Matthew Wilsonb, Marion C.
Dickson, Cesar Ramirez-Molina, Huw Lewis, Rob P. Davis, Donald O. Somers, Margarete
Neu, Emma Jones, Robert Watson
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
a Present address: European Bioinformatics Institute, European Molecular Biology Laboratory, Wellcome Genome Campus, Hinxton,
Cambridge, CB10 1SD, UK
b Present address: AstraZeneca, IMED Biotech Unit, Darwin Building, Cambridge, CB4 0WG, UK
* Corresponding Author. Tel.: +44 1438 763423. E-mail address: mike.d.barker@gsk.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
The discovery and lead optimisation of a novel series of SYK inhibitors is
described. These were optimised for SYK potency and selectivity against Aurora B.
Compounds were profiled in a human skin penetration study to identify a suitable
candidate molecule for pre-clinical development. Compound 44 (GSK2646264)
was selected for progression and is currently in Phase I clinical trials.
2009 Elsevier Ltd. All rights reserved.
Keywords:
SYK
Spleen Tyrosine Kinase
Lead Optimisation
Inhibitor
Skin Penetration
Dermal
Spleen Tyrosine Kinase (SYK) is a 72 kDa cytosolic non-receptor tyrosine kinase that is involved in signal
transduction in a variety of cell types, including B lymphocytes, mast cells and macrophages.1 SYK and Zeta-chain-
associated protein kinase 70 (ZAP-70) are the only members of the SYK family of protein tyrosine kinases and share a
similar domain organisation with two N-terminal SH2 domains and a C-terminal kinase domain. ZAP-70 has much
lower intrinsic enzyme activity and its expression is mainly restricted to T-cells and NK cells.2 SYK plays a key role
in coupling activated immunoreceptors to downstream events that mediate diverse cellular responses, including
proliferation, differentiation and phagocytosis. Inhibition of SYK mediated immunoreceptor (Ig Fc, Ig Fc and B-
cell receptors) signalling leads to the inhibition of mast cell, macrophage and B-cell activation and subsequent release
of inflammatory modulators.3 Therefore, the discovery of safe small molecule SYK inhibitors has attracted much
attention in a number of therapeutic areas, including the treatment of rheumatoid arthritis, B-cell lymphoma and
asthma / rhinitis.4-10
The treatment of several skin diseases such as chronic urticaria, atopic dermatitis and rosacea are inadequately treated
by topically applied medication and the development of a SYK inhibitor which should reduce the overall
inflammatory response could be beneficial if topically applied. Topical administration was preferred over an oral
treatment as drug is applied locally to disease tissue, leading to higher drug levels in the skin whilst minimising the
systemic exposure of drug and hence reducing any potential safety risks.
GSK has investigated several chemical series previously, including the pyrimidine carboxamides11 and the
azanaphthyridines.12 Both templates had developability issues, with several analogues from each series being positive

in the AMES mutagenicity assay.13-14 Additional chemical equity was required to find alternative templates that could
be optimised towards selective SYK inhibitors. To find novel chemotypes, a HTS was run against SYK, using the
SYK lysate assay.15 This is a cell free assay to assess SYK signal transduction with lysates from Ramos B cells.
Concomitantly, a high concentration fragment screen was performed in single shot format at a concentration of 667
M, using an in-house set of lower molecular weight “reduced complexity” molecules. Hits were followed up by full
curve screening in the SYK lysate assay. With previous series, Aurora B activity was evident and this has been
difficult to optimise against during lead optimisation. As this was a potential liability, compounds were screened in
the Aurora B assay too. Hits obtained from the full curve SYK lysate assay were prioritised based on selectivity over
Aurora B, ligand efficiency, novelty and tractability.
From the HTS, a group of novel, ligand efficient compounds were discovered to have SYK activity as exemplified by
compounds 1 and 2. In addition, compound 3 was discovered form the fragment set screening. This was one of the
few fragment hits that didn’t appear more potent at Aurora B and has similar pharmacophoric features to the hits from
the HTS (Table 1).
Table 1. In vitro profile of initial hits
SYK lysate pIC50a,b / ligand
efficiency (LE)c
Aurora B pIC50
cLogP / MW
3.4 / 276
a,b
Compound
1
5.3 / 0.35
4.4
2
5.6 / 0.33
4.0
3.4 / 303
3
4.3 / 0.37
3.9
2.0 / 234
a Enzyme inhibition assay15
b pIC50 values are reported as a mean
c LE= (1.37*pIC50)/n heavy atoms16
Molecular modelling of the compounds in the SYK active site indicated that the likely binding mode was a
monodentate hinge interaction of the pyridine nitrogen with the Ala451 of the hinge region.
Based on these hits demonstrating some selectivity over Aurora B, possessing good ligand efficiency, being novel
starting points and having tractable chemistry, the series was selected for optimisation.
Initial SAR investigations were carried out on 2, varying substitution on the pendant phenyl ring (Table 2).

Table 2. SAR around the pendant phenyl ring
Compound
R
SYK pIC50
5.6
LE
Aurora B pIC50
cLogP / ChromLogDa (pH=7.4)
2
4
5
6
7
8
9
H
0.33
0.26
0.32
0.34
0.31
0.35
0.32
4.0
3.4 / 5.0
3.6 / 5.9
3.9 / 6.0
3.9 / 6.1
3.6 / 5.6
3.3 / 5.3
3.3 / 5.4
2-Me
3-Me
4-Me
4-F
<4.6
5.6
<4.6
<4.6
<4.6
<4.6
4.8*
<4.6
6.1
5.5
4-OMe
3-OMe
6.4
5.8
a ChromLogD (pH=7.4) is the chromatographic LogD obtained at pH=7.4, and is derived from the CHILogD
* 1 value <4.6
The data showed a preference for the phenyl group carrying substitution at the 4-position. Electron donating
substituents at the 4-position, such as the methoxyl depicted in 8, gave the compounds with good potency in the SYK
lysate assay. A 2-substituted analogue, exemplified by 4, was significantly less potent than having the substituent at
the 3- or 4- positions (5 and 6). In addition to the clogP, the chromatographic LogD at pH 7.4 is shown. This is a high
throughput experimental measurement of lipophilicity based on the retention time of the molecule on a reverse phase
HPLC column.
The core aromatic ring was also investigated (Table 3):
Table 3. SAR around the core phenyl ring
Compound
R2
SYK pIC50
LE
Aurora B pIC50
cLogP / ChromLogD (pH=7.4)

8
4-C(O)Me
H
6.4
5.5
5.8
6.1
5.5
5.5
5.5
4.9
5.5
6.0
0.35
0.34
0.34
0.35
0.31
0.33
0.33
0.29
0.33
0.35
4.8*
3.3 / 5.3
3.6 / 6.2
3.1 / 5.8
3.7 / 6.0
3.7 / 6.2
3.9 / 6.2
3.9 / 6.4
3.9 / 6.6
3.8 / 6.7
4.1 / 6.8
10
11
12
13
14
15
16
17
18
5.0
3-OMe
4-OMe
5-OMe
3-F
<4.6
<4.6
<4.6
<4.6
<4.6
<4.6
<4.6
<4.6
4-F
5-F
3-Me
4-Me
* 1 value <4.6
Substituents were tolerated at the 3-, 4- and 5- positions, but most potency was obtained by substitution at the 3- or 4-
positions, particularly with a methoxyl group.
One of the original hits, 1, contained a pyridine core and so a matched pair was synthesised to investigate the effect of
replacing the phenyl group with a pyridyl group (Table 4).
Table 4. Core phenyl replacement
Compound
A
SYK pIC50
5.5
LE
Aurora B pIC50
cLogP / ChromLogD (pH=7.4)
19
20
CH
N
0.36
0.36
<4.6
4.7*
4.2 / 7.0
3.4 / 4.9
5.5*
* 1 value <4.6
As can be seen for compounds 19 and 20, the potency of the phenyl and pyridyl core were the same, but the pyridyl
core was significantly more polar as measured by the ChromLogD. This would give us the option to investigate a
wider range of polarities for our target molecules.
A crystal structure of 20 in human SYK was solved (Figure 1). This confirmed that the pyridine nitrogen is acting as a
monodentate hinge binder to Ala451 as predicted from the modelling. The pendant phenyl group is heading into the
ribose binding pocket of the active site.

Figure 1. X-ray crystal structure of the complex of 20 in the kinase domain of human Spleen Tyrosine Kinase (PDB code 6HM6)
Substitution of the hinge binding group was carried out to investigate the effects on SYK potency (Table 5).
Table 5. SAR around the hinge binding group
a
Compound
R
SYK (LE) / pERK pIC50
5.9 (0.35) / -
<4.6 / -
Aurora B pIC50
cLogP / ChromLogD (pH=7.4)
21
22
23
24
25
H
<4.6
<4.6
4.7
3.4 / 5.0
3.8 / 5.3
3.9 / 5.4
3.9 / 5.5
3.9 / 5.5
3-Me
4-Me
5-Me
6-Me
6.8 (0.39) / 5.0
4.9 (0.28) / -
<4.6 / -
4.8
<4.6
a Inhibition of anti-IgM induced Erk1/2 phosphorylation in Ramos cells15
Variation around the pyridine hinge binding group showed that a methyl group adjacent to the pyridine nitrogen in 25
is not tolerated. The space here in the active site is restricted due to a clash with the carbonyl of Glu449. Compound
22, with the methyl group adjacent to the linker methyloxy chain, was also inactive. This could be due to the preferred
conformation of 22 being twisted and so not being able to bind into the active site in a low energy conformation. The
most potent compound contained the 4-methyl substituent, 23, showing an order of magnitude increase over the 4-H
analogue, 21. This was the most potent and ligand efficient analogue to date and demonstrated 100-fold selectivity
over Aurora B. It was tested in the pERK cellular assay.15 This assay detects the inhibition of anti-IgM induced Erk1/2
phosphorylation in Ramos B cells, the same cell type that is used in the primary SYK lysate assay. Unfortunately, 23
had a large drop off in activity in the cell assay compared to the enzyme assay, almost 2 orders of magnitude.
The effect of adding an additional nitrogen to the pyridine hinge binding motif was carried out to look not only at the
effects on the SYK potency, but also to reduce the lipophilicity of the molecules, as many of the analogues
synthesised so far had been relatively lipophilic (Table 6). There are little data in the literature relating to the optimal
physicochemical space for dermal compounds to penetrate the skin and so it was of interest to span a wider range of
polarities to investigate this.

Table 6. SAR around the heterocyclic hinge binder
Compound
A
SYK (LE) / pERK pIC50
Aurora B pIC50
cLogP / ChromLogD
(pH=7.4)
CLND Solubility
(g/ml)a
8
CH
6.4 (0.35) / <4.3
4.9 (0.27) / -
6.4 (0.35) / -
5.5 (0.30) / -
<4.6 / -
4.8*
<4.6
<4.6
4.7
3.3 / 5.3
2.4 / 4.5
2.4 / 4.7
2.4 / 4.5
2.1 / 4.1
3
26
27
28
29
3 aza
4 aza
5 aza
6 aza
110
11
5
<4.6
7
a Kinetic solubility measured by CLND
* 1 value <4.6
The pyrazine head group, 27, is equipotent with the pyridine head group, 8, and so offers an alternative hinge binder
that contributes to reducing the lipophilicity of the series. Despite the aza analogues decreasing the lipophilicity of the
series, the kinetic solubility as determined in the CLND assay was still only low to moderate. An increase in solubility
is required for the dermal mode of administration.
From the crystal structure, it was apparent that there was additional space and potential interactions that could be
explored in the ribose binding pocket. Previous lead series11,12 had exploited this by targeting a polar triad of residues
with a basic group in an attempt to increase the potency of the compounds. In addition, this change should provide the
enhanced solubility required for a dermal topical formulation.
Initially, an aminoalkyl group was added to the 4-position of the pendant phenyl group to target the polar residues in
the ribose binding pocket (Asp512, Asn499 and Arg498). Disappointingly, the activity against SYK was reduced
compared to the 4-methyl analogue (Table 7). However, the compounds did have reduced lipophilicity and improved
solubility, as expected.
Table 7. Investigation of basic centre on potency
Compound
R
SYK pIC50 (LE)
cLogP / ChromLogD
CLND Solubility (g/ml)

(pH=7.4)
3.9 / 6.1
6
Me
6.1 (0.34)
3
30
31
CH2NH2
CH2CH2NH2
5.6 (0.31)
5.5 (0.29)
2.4 / 1.9
2.7 / 2.1
53
97
Due to the open-chain amino analogues decreasing the ligand efficiency, modelling work was undertaken to
investigate a variety of constrained amines to see which might target 2 of the 3 polar residues in the ribose binding
pocket. Compounds were prioritised and synthesised according to the best fit in the docking studies (Table 8).
Table 8. Investigation of constrained amines
Compound
R
SYK pIC50 (LE)
Aurora B pIC50
cLogP /
CLND Solubility
ChromLogD
(pH=7.4)
(g/ml)
32
5.7 (0.29)
<4.6
2.3 / 2.1
104
33
5.5 (0.28)
<4.6
2.9 / 2.2
>=123
34
6.6 (0.35)
<4.6
2.9 / 2.1
109
35
6.7 (0.33)
<4.6
3.3 / 2.3
69

36
5.5 (0.27)
<4.6
3.3 / 2.3
>=129
37
5.7 (0.28)
<4.6
3.3 / 2.3
67
This shows that constraining the amine in 34 and 35 gave higher potency compared to the equivalent open chain
analogues 30 and 31 (around 1 order of magnitude increase). Additionally, the constrained amine analogues gave
compounds with moderate / high solubility (Table 8).
Although the constrained amino analogues didn’t always offer a significant increase in potency in the SYK lysate
assay over the monosubstituted phenyl analogues, they did however offer improved cellular potency in the pERK
mechanistic assay as demonstrated by the comparison of 38 with 23 (Table 9). The high artificial membrane
permeability data indicate that the drop-off in activity from enzyme to the cell for 23 is not due to passive
permeability. Pleasingly, 38 also maintained the ca. 100-fold selectivity over Aurora B.
38
Table 9. Effect of the constrained amine on the cellular potency
SYK pIC50
pERK pIC50
Aurora B
Artificial membrane
Permeability (nm/s)
CLND solubility
(g/ml)
23
6.8
6.7
5.0
6.3
4.7
330
435
5
38
4.8*
>=153
* 3 values <4.6
Based on these promising cellular data, further combinations with constrained amines were synthesised to investigate
enhancing the cellular potency of the molecules (Table 10).

Table 10. Combination of constrained amine and substitution around the hinge and core groups
Compound
A
R
R2
SYK pIC50 (LE)
pERK
pIC50
Aurora B
pIC50
cLogP / ChromLogD
(pH=7.4)
35
39
40
41
42
43
44
45
46
47
48
C
C
C
C
C
C
C
C
C
N
N
H
4-(CO)CH3
4-(CO)CH3
4-(CO)CH3
4-(CO)CH3
4-CN
6.7 (0.33)
7.4 (0.35)
7.4 (0.34)
6.7 (0.30)
6.5 (0.31)
7.0 (0.32)
7.1 (0.35)
7.2 (0.35)
7.1 (0.35)
6.4 (0.32)
6.7 (0.34)
-
<4.6
5.0
3.3 / 2.3
3.8 / 2.5
4.3 / 2.8
4.2 / 2.7
3.8 / 2.8
3.0 / 1.9
3.6 / 3.1
4.1 / 3.0
4.1 / 3.0
2.1 / 2.2
2.7 / 2.4
Me
Et
6.9
6.6
6.2
6.0
6.5
6.7
6.5
6.2
-
4.9
OEt
Me
Me
Me
Me
Me
-
5.4
4.6
4-(CO)NHMe
3-OMe
4.7
<4.6
4.6*
4.7^
<4.5
<4.6
4-OMe
5-OMe
3-OMe
-
4-OMe
6.4
* 8 values <4.6; ^ 2 values <4.6
Table 10 shows that these constrained analogues are generally potent in the cell assay. The optimal R group for
balancing the SYK lysate potency, the cellular potency and the physicochemical properties is the methyl (compare
compounds 39-41). The R2 group is somewhat more accommodating, and good cellular activity was obtained with
both 3- and 4- substituted analogues such as the methoxyl group in examples 44 and 45.
An X-ray crystal structure of compound 44 in human SYK was solved (Figure 2). This confirmed the hypothesised
interaction between the cyclic amino group with the aspartate residue (Asp512) that forms part of the ribose pocket in
the ATP binding site of SYK.

Figure 2. X-ray crystal structure of the complex of 44 in the kinase domain of human Spleen Tyrosine Kinase (PDB code 6HM7)
Several compounds were profiled in more detail to investigate their suitability as a topical dermal agent. One assay
that was developed to assist with prioritisation was an in vitro human skin penetration assay. The permeability
(percutaneous flux) of two SYK inhibitors 39 and 44 through intact human skin was measured, by applying a 1%
solution of the inhibitors in ethanol: PBS (60:40, v/v) to sections of human skin. Compound 44 was penetrable into
the epidermis and dermis of the skin and showed a 1.5-fold higher concentration in the epidermis compared to 39. The
calculated dermal concentration of compound 44 was 60 M. No significant differences in dermal concentrations
were noted (Figure 3).
Figure 3. Total amounts of 44 and 39 measured in the epidermis and dermis 6h after topical application. The human biological samples
were sourced ethically and their research use was in accord with the terms of the informed consents under an IRB/EC approved protocol.

Compound 44 showed a > 6-fold increase in the cumulative amount of drug material in the receiving fluid after 6 h
compared to 39, indicating that there was a flow of 44 through the skin, reducing the likelihood of accumulation.
(Figure 4)
44
39
Figure 4. Cumulative concentration of 44 and 39 after topical application onto the skin (Error bars represent SEM from n=3 donors with 6
replicates per donor). The human biological samples were sourced ethically and their research use was in accord with the terms of the
informed consents under an IRB/EC approved protocol.
Compound 44 was screened through a number of kinase assays (Table 11) and demonstrated good selectivity (at least
30-fold) against the other kinases shown.
Table 11. Kinase selectivity of 44
Kinase
pIC50
Fold selectivity (by IC50)
SYK
7.1
<4.3
<4.6
4.5
5
-
Aurora A
Aurora B
VEGFR2
JAK2
>630
>316
398
125
63
5.3
5.4
5.4
GSK3
LCK
39
LRRK2
50

Based on the optimal balance of properties, GSK2646264 (44) was chosen as our molecule to progress into pre-
clinical studies.
In summary, we have described a novel series of SYK inhibitors, containing a pyridine or pyrazine hinge binding
group. The compounds demonstrated good SYK lysate potency that transferred well into a mechanistic cellular assay,
as well as demonstrating very good selectivity over a key liability target, Aurora B. A pre-clinical candidate was
identified from this series that has progressed into Phase I clinical studies, and will be the subject of further
publications.
Acknowledgements
The authors wish to thank Michael Woodrow for his input into the chemistry.
Supplementary data
Supplementary data associated with this article, including preparation of 44, crystallography, skin penetration assay
and physicochemical assay protocols, can be found in the online version.
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



A novel series of SYK inhibitors was identified through fragment and HTS screening
This was optimised to give selective inhibitors with good cellular potency
Skin penetration studies were carried out to assess permeability
A pre-clinical candidate was identified that is currently in Phase I clinical studies