Novel non-ATP competitive small molecules targeting the CK2 α/β interface

Article abstract of DOI:10.1016/j.bmc.2018.05.011

Increased CK2 levels are prevalent in many cancers. Combined with the critical role CK2 plays in many cell-signaling pathways, this makes it a prime target for down regulation to fight tumour growth. Herein, we report a fragment-based approach to inhibiting the interaction between CK2α and CK2β at the α-β interface of the holoenzyme. A fragment, CAM187, with an IC₅₀ of 44 μM and a molecular weight of only 257 gmol^?1 has been identified as the most promising compound. Importantly, the lead fragment only bound at the interface and was not observed in the ATP binding site of the protein when co-crystallised with CK2α. The fragment-like molecules discovered in this study represent unique scaffolds to CK2 inhibition and leave room for further optimisation.

Full text of DOI:10.1016/j.bmc.2018.05.011

Accepted Manuscript
Novel non-ATP competitive small molecules targeting the CK2 α/β interface
Paul Brear, Andrew North, Jessica Iegre, Kathy Hadje Georgiou, Alexandra
Lubin, Laura Carro, William Green, Hannah Sore, Marko Hyvönen, David
Spring
PII:
S0968-0896(18)30329-8
https://doi.org/10.1016/j.bmc.2018.05.011
BMC 14353
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 February 2018
7 May 2018
8 May 2018
Please cite this article as: Brear, P., North, A., Iegre, J., Hadje Georgiou, K., Lubin, A., Carro, L., Green, W., Sore,
H., Hyvönen, M., Spring, D., Novel non-ATP competitive small molecules targeting the CK2 α/β interface,
Bioorganic & Medicinal Chemistry (2018), doi: https://doi.org/10.1016/j.bmc.2018.05.011
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Novel non-ATP competitive small molecule
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targeting the CK2 α/β interface
Paul Breara, Andrew Northb, Jessica Iegreb, Kathy Hadje Georgioub, Alexandra Lubinb, Laura Carrob, William
Greenb, Hannah Soreb, Marko Hyvönena and David Springb
a Department of Biochemistry, University of Cambridge, Sanger Building, 80 Tennis Court Road, Old Addenbrooke’s Site, Cambridge, CB2 1GA, UK
b Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK

Bioorganic & Medicinal Chemistry
Novel non-ATP competitive small molecules targeting the CK2 α/β interface
Paul Breara, Andrew Northb, Jessica Iegreb, Kathy Hadje Georgioub, Alexandra Lubinb, Laura Carrob,
William Greenb, Hannah Soreb, Marko Hyvönena and David Springb, 
a Department of Biochemistry, University of Cambridge, Sanger Building, 80 Tennis Court Road, Old Addenbrooke’s Site, Cambridge, CB2 1GA, UK
b Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Increased CK2 levels are prevalent in many cancers. Combined with the critical role CK2
plays in many cell-signaling pathways, this makes it a prime target for down regulation to
fight tumour growth. Herein, we report a fragment-based approach to inhibiting the
interaction between CK2α and CK2β at the α-β interface of the holoenzyme. A fragment,
CAM187, with an IC50 of 44 μM and a molecular weight of only 257 gmol-1 has been
identified as the most promising compound. Importantly, the lead fragment only bound at
the interface and was not observed in the ATP binding site of the protein when co-
crystallised with CK2α. The fragment-like molecules discovered in this study represent
unique scaffolds to CK2 inhibition and leave room for further optimisation.
Available online
Keywords:
CK2
Protein-protein interaction
Fragment based drug discovery
2009 Elsevier Ltd. All rights reserved.
———
 Corresponding author. Tel.: +44 1223 336498; fax: +44 1223 336362; e-mail: spring@ch.cam.ac.uk

1. Introduction
interface site although no crystal structures have been published
to validated this. Additionally, W16 and the diazodinaphthalene
compound are large molecules with some undesirable
physicochemical properties, therefore do not make ideal lead
candidates for further drug discovery (Figure 1).17,18 Finally, a
cyclic peptide, Pc, was found to inhibit the interaction between
CK2α and CK2β.19
1.1. CK2 as a potential target
CK2 is a ubiquitous protein kinase and is overexpressed in a
large range of cancers.1 As a protein kinase, CK2 phosphorylates
many substrates involved in cell growth.2 Unnaturally high
quantities of CK2 and its associated activity have been observed
in many tumours.3 In healthy cells, CK2 is diffused in the various
cellular compartments and is up regulated during cell
proliferation, but readily returns to normal levels. However, in
tumour cells there are high levels of CK2 about the nucleus, and
during cell proliferation, CK2 finds homoeostasis at its new high
level.4,5 CK2, as well as being involved in cell proliferation and
growth, also suppresses apoptosis, linking CK2 to the cancer
phenotype.6
1.3. Ideal chemical fragment
The fragment-based approach to drug discovery utilises small
compounds (molecular weight ≤ 300 gmol-1) to identify starting
points against any target of interest.20 Although fragments may
Scheme 2 (a) Indole-4-boronic acid, K3PO4, PCy3, Pd2(dba)3, 1,4-
dioxane, (b) LiAlH4, AlCl3, Et2O
CK2 inhibition may be a particularly effective form of
treatment as it has a pivotal and indispensable role in the cells. If
inhibited below the high critical threshold, the cancerous cell
would no longer be malignant as there are no alternative
signaling pathways which could by-pass the need for CK2.7 Due
to the role of CK2 in cell growth, proliferation, and apoptosis, its
down regulation is catastrophic to cancer cells. Its validation as
an anti-cancer target is shown in the fact CK2 inhibitors have
entered clinical trials.8
bind with weak affinity they tend to have high intrinsic binding
energy, high ligand efficiency, and readily optimizable
physiochemical properties. These fragments can then be
expanded to increase the potency whist maintaining the
compound’s drug-like properties.21
Due to the usefulness of fragments as a tool for drug
discovery, work has been done to explore the idea of the ideal
chemical fragment. Studies have suggested that a ‘Rule of
Three’22 (mirroring Lipinski’s Rule of Five23) is a useful method
for measuring how ‘fragment-like’ molecules are.
1.2. CK2 inhibition strategies
Previous research into CK2 inhibition has focused on small
molecules that inhibit the kinase activity at the ATP-binding
site.9–11 Strategies that focus on the ATP-binding site for
inhibition often suffer from off-target action due to the highly
conserved nature of the ATP pocket across the genome.12,13
Indeed, the current clinical candidate, CX4945, inhibits CK2 at
the ATP pocket and shows off-target activity against 13 proteins
with nanomolar IC50. Additionally, in one study CX4945 was
shown to inhibit CLK2 more potently than CK2 (3.8 nM
compared to 14.7 nM).14
Herein, we report the discovery of a novel fragment which
binds to the CK2α/CK2β interface pocket. This lead fragment
could be modified to give new CK2 inhibitors that show limited
off-target activity.
2. Material and methods
2.1. Chemistry
2.1.1. Experimental Procedures
Compounds 2, 4, and 5 were synthesised from commercially
available 3-chloro-4-bromobenzonitrile. This was subjected to a
Suzuki-Miyaura cross-coupling with the relevant aryl boronic
acid to produce a biaryl nitrile. This nitrile was reduced to give
the final compounds. Compound 3 was synthesised using a
similar procedure; however, starting from commercially available
3-chloro-4-hydroxybenzonitrile. This was triflated and then
subjected to the above reactions as detailed in Scheme 1.
Alternative strategies to selectively inhibit CK2 have recently
been explored; these exploit other aspects of the protein unique to
CK2. The αD pocket, which is unique to CK2, was discovered
near the ATP site. It has been exploited by linking a low affinity
ATP site fragment to an elaborated fragment in the αD site. This
led to a novel and selective CK2 inhibitor.14,15
Compound 7 was synthesised from commercially available 3-
chloro-5-bromobenzonitrile and indole-4-boronic acid via
Suzuki-Miyaura cross-coupling followed by nitrile reduction as
shown in Scheme 2
2.1.2. Detailed procedures and characterization
Detailed procedures and characterisation of all compounds
reported in this paper and their precursors can be found in the
Supporting Information.
2.2. Biological assays
Figure 1 Three previous inhibitors of the CK2 interface: DRB, W16,
and the diazodinaphthalene compound
Scheme 1 (a) CH2Cl2, Py, Tf2O, (b) ArB(OH)2, K2CO3, DCE,
Pd(PPh3)4, (c) LiAlH4, Et2O, AlCl3. Full procedures are detailed in the
Supporting Information
One of the other areas to probe for non-ATP site inhibition is
the protein-protein interaction (PPI) interface between the
catalytic and regulatory subunits of CK2: CK2α and CK2β. To
date three small molecules and a peptide have been shown to
bind in the interface pocket on CK2α. The fragment, DRB, binds
at both the ATP and the α/β interface site (Figure 1).16 W16 and
a diazodinaphthalene compound are believed to bind at the

Protein expression and purification, X-ray crystallography,
and FP assays can be found in the Supporting Information of this
paper and our recently published papers.14,15
The first iteration explored was substituting the methylamine
group (the red box in Figure 2) to enhance or pick up new
interactions outside the pocket. An additional 12 compounds
were synthesised with a variety of functionality coupled with
alkyl chains of various lengths. Functionality explored were
amines, alcohols, amides, carboxylic acids, dihydroimidazole,
aldehyde, carbamate, as well as compounds with bifunctionality
like an amino alcohol and a diol. Disappointingly, only one of the
methylamino variants (ethylamino, NMR154L) showed minimal
improvement compared to NMR154 (900 μM vs 700μM). As no
significant improvement in binding affinity was observed with
the ethylene analogue, the second iteration of compounds
continued to use the methylene linkage. In addition, these
analogues were easier to synthesise as they required only a
reduction of the nitrile to obtain the final compounds.
Following exploration of the methylene linkage, substitution
on the amine was explored next (the blue box in Figure 2). In
this iteration 26 compounds were made. It was hoped that
elaborating off this position would exploit any new H-bond
interactions, in addition to maintaining the interaction with
Asp37. Thus, a variety of alcohols were chosen as well as a
carbamide, amine, imidazole, amide, and morpholine. Again,
none of the nitrogen substituted analogues showed an
improvement upon NMR154 (details given in Supporting
Information).
3. Results and Discussion
3.1. Initial hits of NMR154
The Abell Research Group (at Cambridge University)
conducted initial high throughput screening of fragments from
their fragment library against CK2 using an FP (fluorescence
polarization) assay. This library consisted of over 400
compounds from the Abell Group. The most promising fragment
from this screen was NMR154 (Figure 2).24 This compound was
found to bind in both the ATP pocket and the α-β interface site.
Having investigated variations of the methylene linkage and
amino group substitution, further studies were made into varying
other parts of the benzene ring (the vectors highlighted in green
in Figure 2). From the crystal structures we expected that
modification of the substituents and the aryl group itself would
result in a better fit in the pocket and therefore increased binding
affinity. At total of 16 compounds were synthesised. A selection
of aromatic and aliphatic groups were chosen including a variety
of substituted benzene rings, a naphthalene, and a pyrrole. A
range of ethers were also tested with alkyl groups and an amine.
A crystal structure was obtained of NMR154L, the ethyl
analogue of NMR154, (Figure 3a) showed a molecule each
binding in the interface pocket as well as the ATP site and the αD
site. This showed the dichlorobenzene part of the molecule
anchoring in the pocket while the ethylamino moiety protruded
from the pocket to interact with an aspartate residue of the
protein (Asp37 is on the edge of the α-β interface site and forms a
salt bridge with Arg186 from CK2β).
With this crystal structure in hand, it was hoped that the
binding could be improved by modifying NMR154 along a series
of vectors, utilizing anchoring in the pocket and increasing the
interactions outside the pocket with the protein residues (Figure
2).
Pleasingly, this substitution showed the greatest improvement
in inhibition with all the dibenzene compounds showing an IC50
of less than 500 μM (see Supplementary Information).
Unfortunately, the pyrrole and aliphatic compounds showed no
improvement. This would suggest that the greatest improvement
to be made to NMR154 would be to more firmly anchor it into
3.2. Fragment development
Figure 2 A selection of the analogues of NMR154 synthesised. The analogues in the blue box maintained all the features of NMR154 but added
additional functionality onto the nitrogen. The red box shows analogues which kept the dichlorobenzene moiety but substituted the methylamine for the
groups shown. Finally, the green box shows substitutions made to the chlorine highlighted in green

the pocket rather than to utilising bonding interactions with
residues outside the pocket.
Pleasingly, these judgements were correct, and the new
fragment, CAM187, gave the best IC50 of 44 μM. A crystal
structure of the fragment using the CK2α construct CK2a_KA
showed it only bound in the interface pocket. The Cl fills the
phenyl pocket and the amine interacts with Asp37 as with the
original fragment. Whereas, the indole ring sits under the β4β5
loop and the nitrogen of the indole interacts with the OH group of
THR108. (Figure 3d).
A crystal structure of 3 binding in the pocket was obtained
(Figure 3b). This clearly showed that the electrostatic interaction
between the amino moiety and Asp37 was maintained. In
addition, the 2-isopropylbenzene moiety is occupying the pocket
both in terms of depth and width. However, for the biaryl
compounds, electron density was also observed in the αD site.
3.3. Improving selectivity for α/β interface binding only
Table 1 Summary of compounds with improved binding
Compound
Structure
clogPa IC50 (μM)b
The αD pocket being deep and narrow favours the para
disposition of the aryl ring and the methylamino.15 In order to
improve selectivity so that the fragments only bound at the α/β
interface a series a meta disposed compound was synthesised and
tested.
NMR154
2.60
3.49
900
150
This hypothesis was shown to be correct, and the meta biaryl
compound tested bound exclusively at the interface (entry 6 in
Table 1).
Although having a high IC50 of 3 mM examination of the
crystal structure of compound 6 showed the biaryl core lying on
its side taking up the width of the pocket with the amine
interacting with Asp37 (Figure 3c). It was theorized that
increasing the size of the pyrrole to an indole would occupy more
of the depth of the pocket increasing the potency of the fragment.
In addition, a chlorine on the benzene ring was removed to
decrease the clogP (calculated logarithm of the partition
coefficient).
2
Figure 3 A side-by-side depiction of five fragments binding in the interface site of CK2α. a) NMR154L binds so that the dichloro moiety anchors the fragment
into the hydrophobic pocket (pdb:5CLP). The ethylamino group juts out of the pocket to form an H-bond with Asp37 outside the pocket.b) Compound 3
maintains the H-bond with Asp37. The second aromatic ring provides a better hydrophobic interaction in the pocket as it occupies more of the space. c)
Compound 6 shows some promise as an interface binder. The interaction with Asp37 is maintained as well as the biaryl core occupying the width of the pocket.
It is clear from the image there is an unoccupied area of the pocket beneath the pyrrole ring. This is a potential area for growth. d) The lead fragment CAM187
(7), like its predecessors, forms an H-bond with Asp37. This time with the aid of a bridging water molecule. In indole moiety provides the best hydrophobic
interactions out of the molecules tested. It provides both the with to fill the pocket as well as the depth to fill it.

319
2.2
87.7
6
257
3.45
41.8
2
<500
≤5
611
2
439
2.2
165
10
3
MW
clogP
PSA
HBA
HBD
RBC
CC
<300
≤3
≤140
≤10
≤5
133
11
1
≤ 60
≤3
3
4.60
205
3
3
≤3
5
3
<10
7
6
≤3
3
0
5
0
0–1
No
Yes
No
No
No
ATP
4
5
3.86
3.19
208
493
4. Conclusion
By screening the NMR compound library an initial hit was
found for an inhibitor of the PPI between the α-β subunits of
CK2 with an IC50 of 900 μM. This compound was modified and
elaborated through several vectors. Through five iterations, 63
compounds were synthesised and tested against CK2. Through
the first three iterations (elaborating at each of the vectors
highlighted in Figure 2), it was found that a series of biaryl
compounds were the best inhibitors of the PPI with the lead
compound at that stage (2) giving an IC50 of 150 μM. Realising
this trend additional biaryl compounds were screened against
CK2 to give the lead compound, CAM187 (7). These compounds
affect their binding by the biaryl part of the molecule filling the
PPI pocket on the protein and the pendent ammonium group
forming an H-bond with an Asp37 above the pocket.
6
2.91
3.45
3000
CAM187 is the first small molecule fragment to inhibit the α-
β interface of CK2 without also binding in the ATP site. Due to
its fragment-like properties, CAM187 leaves room for further
development. These developments could lead to drug-like
molecules with high potency and selectivity against CK2 as well
as deeper understanding between the structure activity
relationship.
7
44
Acknowledgments
CAM187
We would like to thank the X-ray crystallographic facility and
the Biophysics facility at the Department of Biochemistry for
support and access to equipment. We thank Diamond Light
Source for access to beamlines. Instant JChem was used for
structure database management and searching, Instant JChem
16.10.10.0, 2016, ChemAxon (http://www.chemaxon.com). This
work was funded by the European Research Council under the
European Union’s Seventh Framework Programme (FP7/2007-
2013)/ERC grant agreement no [279337/DOS] (to DRS)
a calculated of partition coefficient. b half maximal inhibitory
concentration.
CAM187 has advantages over previously discovered interface
inhibitors because of its fragment-like nature (see Table 2). W16
(IC50 ≈ 20 μM)17 and the diazo compound (IC50 ≈ 0.4 μM)18 are
already at the top end for molecular weight and leave little room
for elaboration to improve their potency and drug-like properties.
likely exhibit undesired biological properties.25 Further analysis
of CAM187 showed that it did not inhibit the phosphorylation
activity of CK2α at 100 μM. (% inhibition 18% at 100μM). This
confirms that CAM187 does not significantly bind in the ATP
site of CK2 at these concentrations.
and the Wellcome Trust
Strategic
(090340/Z/09/Z)
and
Pathfinder (107714/Z/15/Z) Awards (to DRS and MH). In
addition, the Spring group research was supported by grants from
the Engineering and Physical Sciences Research Council,
Biotechnology and Biological Sciences Research Council,
Medical Research Council and the Royal Society. JI would like
to thank Trinity College, University of Cambridge for funding.
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