Discovery and optimization of novel benzothiophene-3-carboxamides as highly potent inhibitors of Aurora kinases A and B

Article abstract of DOI:10.1016/j.bmcl.2018.05.064

Aurora kinases as regulators of cell division have become promising therapeutic targets recently. Here we report novel, low molecular weight benzothiophene-3-carboxamide derivatives designed and optimized for inhibiting Aurora kinases. The most effective compound 36 inhibits Aurora kinases in vitro in the nanomolar range and diminishes HCT 116 cell viability blocking cytokinesis and inducing apoptosis. According to western blot analysis, the lead molecule inhibits Aurora kinases equipotently to VX-680 (Tozasertib) and similarly synergizes with other targeted drugs.

Full text of DOI:10.1016/j.bmcl.2018.05.064

Accepted Manuscript
Discovery and optimization of novel benzothiophene-3-carboxamides as highly
potent inhibitors of Aurora kinases A and B
Pál Gyulavári, Bálint Szokol, István Szabadkai, Diána Brauswetter, Péter
Bánhegyi, Attila Varga, Péter Markó, Sándor Boros, Eszter Illyés, Csaba
Szántai-Kis, Marcell Krekó, Zsófia Czudor, László Őrfi
PII:
S0960-894X(18)30477-3
https://doi.org/10.1016/j.bmcl.2018.05.064
BMCL 25881
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 February 2018
28 May 2018
31 May 2018
Please cite this article as: Gyulavári, P., Szokol, B., Szabadkai, I., Brauswetter, D., Bánhegyi, P., Varga, A.,
Markó, P., Boros, S., Illyés, E., Szántai-Kis, C., Krekó, M., Czudor, Z., Őrfi, L., Discovery and optimization of
novel benzothiophene-3-carboxamides as highly potent inhibitors of Aurora kinases A and B, Bioorganic &
Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.05.064
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Discovery and optimization of novel
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benzothiophene-3-carboxamides as highly
potent inhibitors of Aurora kinases A and B
O
O
NH2
NH2
H
4
N
3
Aurora A IC50: 32 ± 17 nM
Aurora B IC50: 29 ± 14 nM
S
H
N
S
5
6
O
2
H
O
S
N
S
O
7
1
36

Bioorganic & Medicinal Chemistry Letters
Discovery and optimization of novel benzothiophene-3-carboxamides as highly
potent inhibitors of Aurora kinases A and B
Pál Gyulavária‡, Bálint Szokolb‡, István Szabadkaib, Diána Brauswettera, Péter Bánhegyib, Attila Vargaa,
Péter Markób, Sándor Borosb, Eszter Illyésb, Csaba Szántai-Kisb, Marcell Krekóc, Zsófia Czudorc, László
Őrfib,c 
aMTA-SE Pathobiochemistry Research Group, 37-43. Tűzoltó u., Budapest, 1094, Hungary
bVichem Chemie Research Ltd., 15. Herman Ottó u., Budapest, 1022, Hungary
cDepartment of Pharmaceutical Chemistry, Semmelweis University, 9. Hőgyes Endre u., Budapest, 1092, Hungary
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Aurora kinases as regulators of cell division have become promising therapeutic targets recently.
Here we report novel, low molecular weight benzothiophene-3-carboxamide derivatives
designed and optimized for inhibiting Aurora kinases. The most effective compound 36 inhibits
Aurora kinases in vitro in the nanomolar range and diminishes HCT 116 cell viability blocking
cytokinesis and inducing apoptosis. According to western blot analysis, the lead molecule
inhibits Aurora kinases equipotently to VX-680 (Tozasertib) and similarly synergizes with other
targeted drugs.
Keywords:
cancer
targeted therapy
aurora kinase
2018 Elsevier Ltd. All rights reserved.
kinase inhibitor
benzothiophene-3-carboxamide
———
‡ These authors contributed equally.
 Corresponding author. Tel.: +36 20 6259625; e-mail: orfi.laszlo@pharma.semmelweis-univ.hu

During the last one and a half decades, kinases have become
the most important targets in cancer therapy. However, the higher
efficiency and lower toxicity of kinase inhibitors can be observed
only in a subpopulation of patients with overexpression or
mutation of the particular kinase. Such potential targets are the
serine-threonine Aurora kinases (A and B), which were proven to
play an important role in the regulation of cell division.1,2
Aurora A the ’polar kinase’1 is located at the centrosome and
is required for its maturation, division, for the mitotic spindle
assembly and entry into mitosis.3,4 Mutation or transcriptional
silencing of Aurora A impairs centrosome maturation and
separation, leads to mono/multipolar spindles, to delayed mitotic
entry5 and even to apoptosis in some experiments.6,7 On the other
hand, amplification of the AURKA gene and overexpression of
Aurora A protein causes multipolar spindles, cytokinesis failure,
thus chromosomal aberrations and increased resistance to
apoptosis in cellular8,9 and in in vivo models.10 Indeed, AURKA
gene amplification and Aurora A protein overexpression is a
common phenomenon in various human tumors and correlates
with poor prognosis.11-15
The notion that overfunctioning Aurora A and B kinases can
significantly contribute to the growth of malignancies, led to the
development of several Aurora A and/or Aurora B inhibitors.24-26
In this paper we report on the design, synthesis and biological
evaluation of a series of new, small molecular weight kinase
inhibitors. We show that these compounds inhibit Aurora kinase
activity and diminish cell viability by inducing apoptosis
comparable to reference compounds VX-680 and MLN8054,
providing the first benzothiophene-3-carboxamide-based Aurora
kinase inhibitors reported so far.
Figure 1. Structure of the primary hit, compound 10. Circles indicate
sites of modifications.
Aurora B the ’equatorial kinase’1 is required for chromosome
condensation in the prophase,16 for the spindle assembly
checkpoint in the inner centromere regions,17 for chromosome
segregation during metaphase and for cytokinesis itself at the
central spindle.18 Depletion or inhibition of Aurora B kinase
activity causes omission of cytokinesis, multi-nucleated
polyploid cells and ultimately apoptosis.19-21 The AURKB gene is
not commonly amplified, or mutated,22 however overexpression
of Aurora B protein has been reported in many cancer cell lines
and tumor types.23
We have carried out preliminary in vitro recombinant Aurora
A and B kinase assays utilizing the in-house compound
collection of Vichem Ltd. and identified the benzothiophene-3-
carboxamide derivative 10 (Figure 1) which showed
submicromolar activity against Aurora A (IC50=827 nM (IC50:
half maximal inhibitory concentration)) and Aurora B (IC50=417
nM). Introducing subtle modifications at three different positions
(R1, R2 and R3), we designed and synthesized several derivatives
of 10 to get more potent small molecular weight Aurora kinase
inhibitors.
Our analogs were prepared according to the scheme shown in
Figure 2.
Figure 2. Preparation of benzothiophene-3-carboxamide derivatives. a: acetone, 1% aqueous NaOH, 60°C; b: diethyl malonate, NaOMe, methanol, reflux,
then 37% HCl, reflux; c: NH4OAc, toluene or NH3(g)/benzene, reflux; d: 60% NaH, Boc2O, 0°C; e: THF, cyanoacetamide, TiCl4, 0°C; f: S (powder), morpholine
or NaHCO3, ethanol, reflux; g: cyclopropanoyl chloride, THF, pyridine, 0°C; h: TFA or HCl, RT; i: R3-SO2Cl, pyridine; j: phenyl-chloroformate, THF, pyridine,
RT, then MeNH2; k: TFA or HCl/ethyl acetate, RT, 20 min; l: R3-SO2Cl, pyridine.

Inhibition of Aurora A compromises mitotic progression, thus
cell viability; while inhibition of Aurora B abrogates cytokinesis
and induces polyploidy that leads to apoptosis of most cells.
Given the well-known discrepancy between compound potencies
in biochemical and cell-based assays, we decided to screen the
derivatives of 10 at first on cell lines as others did.27 The well-
known HCT 116 cell line was used to investigate the structure-
activity relationship. We could make the following assertions: i)
Regarding the cyclopropanoyl-amino series (Table 1) R3 was
represented with different kind of substituents, namely aryl,
alkyl, cycloalkyl and heteroaryl groups. Only replacement of the
R3 phenyl group of 10 to methylpyrazol (16) augmented cell
viability inhibition. ii) Fixing R2 group as methylamine (Table 2)
and varying the R3 substituents increased cell viability inhibition
significantly in most of the cases (10 vs. 20, 13 vs. 28, 14 vs. 29,
15 vs. 36 and 17 vs. 22), but did not in two cases (12 vs. 27 and
16 vs. 42). Among these methylureido derivatives eight
compounds inhibited HCT 116 cell viability better than 16 (<0.76
µM). iii) Substitution of the R3 benzene ring of 20 was tolerable
in the case having methyl group at meta position only (22). iv) Of
the short alkyl substituents of R3 only ethyl (28) and n-propyl
(29) chains approximated the cellular effect of 20. v) A
secondary or tertiary amine side chain at R3 (33 and 32) was
equally effective to 20 so definitely more favorable than the alkyl
chains of similar shape and size (31 and 30). vi) Having
heterocyclic substituents at position R3, the 2-furan bearing
derivative (34) showed weaker effect than the methylpyrazole
(42) or 2-thiophene (36) derivatives, the latter being slightly
more potent than 20. vii) Similarly to the R3-phenyl substitution,
a methyl group on the thiophene ring was tolerable at position 4
only, but not at position 5 (39 vs. 40). viii) Swapping the R1
isopropyl group to methyl or cyclopropyl group abolished the
cellular effect (36 vs. 37 and 38, 42 vs. 43 and 44). ix) The R2
cyclopropyl to methylamine exchange slightly improved the
cellular effect in case of the R3-methylpyrazol derivatives as well
(16 vs. 42).
To prove that the mechanism of action of the eight hit
compounds indeed involve inhibition of Aurora kinases we
performed in vitro recombinant Aurora A and B kinase assays.
Most molecules had a better IC50 value than VX-680 on both
kinases. However, we did not detect considerable differences
between the eight hit compounds and their Aurora A or B
inhibition values (Table 3).
Table 3. IC50 values of the hit compounds in in vitro recombinant Aurora A
and B kinase assay. Values are the mean of at least three independent
experiments ± standard deviation (SD).
Enzymatic assay IC50 ± SD [nM]
ID
Aurora A
Aurora B
37 ± 17
35 ± 14
20
22
95 ± 15
24 ± 12
9 ± 3
46 ± 26
38 ± 11
23 ± 16
11 ± 6
28
32
21 ± 7
33
32 ± 17
80 ± 37
5 ± 1
29 ± 14
48 ± 23
17 ± 9
36
39
42
VX 680
127 ± 38
43 ± 31
Appearance of multinucleated, polyploid cells is a hallmark of
Aurora B inhibition that triggers apoptosis in time. We utilized
flow cytometry to detect the impact of the hit compounds on the
apoptotic fraction of HCT 116 cells (Figure 3). Interestingly,
only hit compounds harboring benzene or heterocyclic side
groups at position R3 (20, 22, 36, 39, 42) and the pan-Aurora
inhibitor VX-680 induced apoptosis at 100 nM, whereas
compounds bearing alkyl or alkyl-amine functions at position R3
(28, 32, 33) and the dedicated Aurora A inhibitor MLN8054 did
not. Exactly the same pattern was observed when DNA content
of cell cultures was measured by flow cytometry: only
compounds with cyclic side groups and VX-680 inhibited
cytokinesis at 100 nM (Supplement Figure 59). It is worth
mentioning that at higher concentration (1 µM) also compounds
with alkyl or alkyl-amine R3 groups and MLN8054 inhibited
cytokinesis and triggered apoptosis (data not shown) as latter
already indicated by others.28
To sum up, the cell viability data on HCT 116 cell line
provided us consequent and clear structure-activity relationship
unlike HCT-15 data (Supplement Table 1). So according to the
HCT 116 experiments we chose eight hit compounds for further
investigations with an IC50 value below 0.6 µM. These cellular
effects are comparable to, or surpass the pan-Aurora inhibitor
VX-680 and the Aurora A inhibitor MLN8054.
Table 1. The cyclopropanoyl-amino series. Core structure and inhibition of
cell viability of compounds 10-17 on HCT 116 cell line. Values are the mean
of at least three independent experiments standard deviation (SD).
O
NH2
H
R3
N
S
H
N
O
O
S
O
IC50 ± SD
[µM]
IC50 ± SD
[µM]
ID
R3
ID
R3
1.39 ± 0.96
6.20 ± 1.10
10
14
9.98 ± 0.03
1.39 ± 0.29
2.36 ± 0.32
4.58 ± 1.03
0.76 ± 0.23
9.01 ± 0.99
11
12
13
15
16
17
S
Figure 3. Fraction of HCT 116 cells undergoing apoptosis measured by
Annexin V-FITC staining after 72
h treatment at 100 nM inhibitor
CH3
N
N
concentrations. DMSO, vehicle control. Values are the mean of three
independent experiments. Error bars represent standard deviation (SD),
*denotes significant difference compared to DMSO (p<0.05) using Student’
t-test.

To further corroborate whether these cellular effects are the
results of in vivo Aurora kinase inhibition, we performed
immunoblotting experiments with the most effective apoptosis-
inducing inhibitor, 36. Western blot analysis revealed that 36
reduced phosphorylation of both Aurora A and B in line with the
reference compound VX-680 as well as the phosphorylation of
histone H3, a well-known Aurora B substrate (Figure 4). In
concordance with the flow cytometry experiments, compounds
bearing alkyl or alkyl-amine side chain at R3 (e.g. 32) and
MLN8054 inhibited both Aurora A and B phosphorylation only
over 100 nM (data not shown). These findings cannot help to
decide which Aurora kinase is the most eligible drug target in
cancer therapy.29 Nevertheless inhibition of Aurora B and
dephosphorylation of Histone-H3 was necessary for apoptosis
induction on HCT 116 cells.
Figure 4. Cellular activity of Aurora kinases A, B and histone H3 after
treatment with various concentrations of 36 and VX-680 a pan-Aurora
inhibitor. Representative blot of three independent experiments on HCT 116
cell line
Table 2. The methylureido series. Core structure and cell viability inhibition of compounds 20-44 as well as VX-680 and MLN8054 as reference Aurora kinase
inhibitors on HCT 116 cell line. Values are the mean of at least three independent experiments ± standard deviation (SD).
O
NH2
H
R3
N
S
H
N
O
O
H
N
S
R1
O
ID
20
21
22
23
24
R1
R3
IC50 ± SD [µM]
0.31 ± 0.16
1.77 ± 0.78
0.47 ±0.34
ID
R1
R3
IC50 ± SD [µM]
1.30 ± 0.48
0.95 ± 0.19
0.29 ± 0.17
0.79± 0.07
34
35
36
37
38
O
O
S
S
S
CH3
CH3
3.80 ± 1.17
3.41 ± 1.41
Cl
1.53 ± 0.41
1.02 ± 0.42
0.34 ± 0.17
25
39
Cl
Cl
S
7.00 ± 3.13
1.47 ± 0.22
0.60 ± 0.05
0.77 ± 0.29
2.33 ± 1.01
2.36 ± 0.22
0.56 ± 0.29
9.78 ± 0.24
26
27
28
29
40
41
42
43
S
S
N
N
CH3
CH3
N
CH3
N

N
2.58 ± 0.43
0.95 ± 0.35
0.30 ± 0.09
0.41 ± 0.22
1.19 ± 0.43
0.45 ± 0.15
0.85 ± 0.07
30
31
32
33
44
N
VX 680
MLN8054
N
H
N
Kinase selectivity panel. Assessment of kinase selectivity of
32 and 36 was performed by Proteros GmbH (Supplement Table
2). Compound 36 is definitely a more broad-spectrum inhibitor
than VX-680.30 At the same time main off-targets of 36 are
receptor-kinases (AXL, VEGFR2, PDGFR-b, DDR1)
deregulated in many cancer types, or c-Src whose simultaneous
inhibition is found to be advantageous.31 According to the kinase
inhibition profile both 32 and 36 have more off-targets than VX-
680. 32 seems to be the more selective one, it inhibits only c-Src,
ABL, RET effectively at 1 µM. However, the simultaneous
inhibition c-Src is known to be advantageous. While 36 seems to
have more off-targets, this effect may be the consequence of
higher screening concentration (10 µM). Fortunately, the off-
targets of 36 are mostly receptor-kinases (AXL, VEGFR2,
PDGFR-b, DDR1) which are also deregulated in many cancer
types.30, 31
nitrogens of R2 form hydrogen bonds with the backbone carbonyl
oxygen of the aforementioned alanine. iii) The oxygen of the
sulfonamide group interacts with the catalytic lysine residue. A
number of further hydrogen bonds were identified in our models,
namely, with the residues D274 of the DFG-motif, R137 and
R220 in Aurora A, and with A217 in Aurora B, in which a π-π
stacking between the benzothiophene ring and F88 is also
present. The docking scores belonging to the binding modes of
36 shown in TOC were comparable to the lowest scores of VX-
680, with -10.894 kcal/mol for 36 vs. -10.587 kcal/mol for VX-
680 in Aurora A, and -9.054 kcal/mol for 36 vs. -9.224 kcal/mol
for VX-680 in Aurora B.
Simultaneous targeting of multiple pathways seems to be a
favorable approach in modern cancer therapy.33 Therefore we
treated HCT 116 cells with 36 or VX-680 in combination with
various other drugs. According to the calculated combination
indexes 36 synergized with most drugs on HCT 116 or HT-29
cells just like VX-680 (Supplement Table 3). A few differences
could be noted: unlike VX-680 36 did not synergize with GSK
and Dasatinib (on HCT 116). In turn 36 synergized with
Lonafarnib (on HCT 116), while VX did not. Consequently 36
behaved similarly to a dedicated pan-Aurora inhibitor in this
experiment which further underlines the Aurora inhibition
properties of 36.
To reveal the possible binding interactions, we docked 36 into
the active site of Aurora A (PBD ID: 4J8M) and Aurora B-
INCENP (PDB ID: 4AF3) structures (Figure 5), and observed
similar binding properties in both isoforms: i) The 3-carboxamide
moiety forms hydrogen bonds with the backbone -NH and the
carbonyl oxygen of the ATP-binding alanine and glutamine
residues of the hinge region respectively (A213 and E211 in
Aurora A; A157 and E155 in Aurora B), which are considered to
be the key interactions necessary for inhibitory activity.32 ii) The
Figure 5. Docking of 36 into the ATP-binding site of Aurora A (PBD ID: 4J8M) and Aurora B-INCENP (PDB ID: 4AF3) crystal structures.
According to RP-HPLC analysis of some compounds
(including the eight hit compounds) the water solubility of
benzothiphene-3-carboxamide derivatives is yet to be improved
(Supplement Table 4). However, the eight hit compounds
excreted their effect at such low concentrations that we could use
them under the solubility limits during all the biological tests.

17. Kallio, M.J.; et al. Inhibition of aurora B kinase blocks
chromosome segregation, overrides the spindle checkpoint, and
perturbs microtubule dynamics in mitosis. Curr Biol, 2002, 12,
900.
18. Lens, S.M.; et al. Shared and separate functions of polo-like
kinases and aurora kinases in cancer. Nat Rev Cancer, 2010, 10,
825.
19. Hauf, S.; et al. The small molecule Hesperadin reveals a role for
Aurora B in correcting kinetochore-microtubule attachment and in
maintaining the spindle assembly checkpoint. J Cell Biol, 2003,
161, 281.
20. Ditchfield, C.; et al. Aurora B couples chromosome alignment
with anaphase by targeting BubR1, Mad2, and Cenp-E to
kinetochores. J Cell Biol, 2003, 161, 267.
Despite many efforts there is still no Aurora inhibitor drug on
the market. In this paper we chart a completely new,
benzothiophene-3-carboxamide scaffold as promising base
structure of Aurora kinase inhibitors. Eight hit of the thirty-two
investigated derivatives inhibited HTC 116 cell viability in the
micromolar range. Despite their similar nanomolar IC50 values in
in vitro Aurora kinase assays, hit compounds arrested cytokinesis
and induced apoptosis of HCT 116 cells differently at low
concentrations. The most potent compound, 36 indeed exerted its
effect through cellular Aurora A and B inhibition as suggested by
western blot analysis. Also, in combination with other targeted
drugs 36 showed similar features to Tozasertib, so qualifies as
the lead molecule of this novel Aurora kinase inhibitor family.
21. Ratushny, V.; et al. Dual inhibition of SRC and Aurora kinases
induces postmitotic attachment defects and cell death. Oncogene,
2012, 31, 1217.
Acknowledgment
22. Fernandez-Miranda, G.; et al. Genetic disruption of aurora B
uncovers an essential role for aurora C during early mammalian
development. Development, 2011, 138, 2661.
23. Hegyi, K.; et al. Mitotic failures in cancer: Aurora B kinase and its
potential role in the development of aneuploidy. Pathol Oncol
Res, 2012, 18, 761.
We thank István Varga for the recording of HPLC-MS
chromatograms and spectra, Kinga Pénzes, and Nóra Breza for
adjusting the in vitro kinase assay.
24. Kollareddy, M.; et al. Aurora kinase inhibitors: progress towards
the clinic. Invest New Drugs, 2012, 30, 2411.
25. Gizatullin, F.; et al. The Aurora kinase inhibitor VX-680 induces
endoreduplication and apoptosis preferentially in cells with
compromised p53-dependent postmitotic checkpoint function.
Cancer Res, 2006, 66, 7668.
26. Manfredi, M.G.; et al. Antitumor activity of MLN8054, an orally
active small-molecule inhibitor of Aurora A kinase. Proc Natl
Acad Sci U S A, 2007, 104, 4106.
27. Geuns-Meyer, S.; et al. Discovery of N-(4-(3-(2-aminopyrimidin-
4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)p
hthalazin-1-amine (AMG 900), a highly selective, orally
bioavailable inhibitor of aurora kinases with activity against
multidrug-resistant cancer cell lines. J Med Chem, 2015, 58, 5189.
28. De Groot, C.O.; et al. A Cell Biologist's Field Guide to Aurora
Kinase Inhibitors. Frontiers in oncology. 2015, 5, 285.
29. Carry, J.C.; et al. SAR156497, an exquisitely selective inhibitor of
aurora kinases. J Med Chem, 2015, 58, 362.
30. Harrington, E.A.; et al. VX-680, a potent and selective small-
molecule inhibitor of the Aurora kinases, suppresses tumor growth
in vivo. Nat Med, 2004, 10, 262.
31. Arai, R.; et al. Simultaneous inhibition of Src and Aurora kinases
by SU6656 induces therapeutic synergy in human synovial
sarcoma growth, invasion and angiogenesis in vivo. Eur J Cancer,
2012, 48, 2417.
This work was supported by FP7 LUNGTARGET (259770)
and KMR-12-1-2012-0074 grants.
This project has received funding from the European Union's
Seventh Framework Programme HEALTH. 2011.2.1.1-2 (Project
title: Proteins and their interactions in health and disease,
PRIMES), Contract number: 278568, and the NVKP_16-1-2016-
0005 (Oncogenomic Project).
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Highlights
•
Two lead compounds were tested against
kinase selectivity panel including 35 kinases.
•
•
The most effective compounds tested
against two cancer cell lines proved to be
specifically sensitive to Aurora kinases.
The synergistic effect of Aurora inhibitors
was examined with various driver
oncogenes.