SAR and evaluation of novel 5H-benzo[c][1,8]naphthyridin-6-one analogs as Aurora kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2013.03.008

Several potent Aurora kinase inhibitors derived from 5H-benzo[c][1,8] naphthyridin-6-one scaffold were identified. A crystal structure of Aurora kinase A in complex with an initial hit revealed a binding mode of the inhibitor within the ATP binding site and provided insight for structure-guided compound optimization. Subsequent SAR campaign provided a potent and selective pan Aurora inhibitor, which demonstrated potent target modulation and antiproliferative effects in the pancreatic cell line, MIAPaCa-2. Furthermore, this compound inhibited phosphorylation of histone H3 (pHH3) in mouse bone morrow upon oral administration, which is consistent with inhibition of Aurora kinase B activity.

Full text of DOI:10.1016/j.bmcl.2013.03.008

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3081–3087
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
SAR and evaluation of novel 5H-benzo[c][1,8]naphthyridin-6-one
analogs as Aurora kinase inhibitors
⇑
Srinivasa Karra , Yufang Xiao, Xiaoling Chen, Lesley Liu-Bujalski, Bayard Huck, Amanda Sutton,
Andreas Goutopoulos, Ben Askew §, Kristopher Josephson , Xuliang Jiang, Adam Shutes à,
Vikram Shankar, Tom Noonan, Gaianne Garcia-Berrios, Rong Dong, Mohanraj Dhanabal, Hui Tian,
Zhenxiong Wang –, A. Clark, Samantha Goodstal
EMD Serono Research Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Several potent Aurora kinase inhibitors derived from 5H-benzo[c][1,8]naphthyridin-6-one scaffold were
identified. A crystal structure of Aurora kinase A in complex with an initial hit revealed a binding mode of
the inhibitor within the ATP binding site and provided insight for structure-guided compound optimiza-
tion. Subsequent SAR campaign provided a potent and selective pan Aurora inhibitor, which demon-
strated potent target modulation and antiproliferative effects in the pancreatic cell line, MIAPaCa-2.
Furthermore, this compound inhibited phosphorylation of histone H3 (pHH3) in mouse bone morrow
upon oral administration, which is consistent with inhibition of Aurora kinase B activity.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 3 December 2012
Revised 21 February 2013
Accepted 4 March 2013
Available online 13 March 2013
Keywords:
Aurora kinase inhibitors
Cancer
Aurora kinase A
Aurora kinase B
Benzonapthyridinones
DFG-out confirmation
Endoreduplication
phosphorylation of histone H3
Aurora kinases A, B and C belong to the serine/threonine protein
kinase family, and are expressed during cell mitosis. Aurora kinase
A plays an essential role in centrosome duplication, maturation
and mitotic spindle assembly.1 Aurora kinase B is the key regulator
of chromosome segregation and cytokinesis.2 Aurora kinase C is a
chromosomal passenger complex protein and co-localizes with
Aurora kinase B throughout mitosis.3 Deregulation of Aurora ki-
nase activity causes mitotic abnormalities leading to genomic
instability, and ultimately tumorigenesis.4 Both the expression
and the activity of Aurora kinases are found to be upregulated in
a wide range of human cancers, including breast, pancreatic, ovar-
ian and colon tumors, indicating that these kinases might serve as
useful targets for the development of anticancer drugs.5 Because of
the possible role of Aurora kinases in cancer etiology, a number of
small molecule Aurora kinase inhibitors have been developed.6,7
Among these, VX-680 (1) was the first Aurora inhibitor to show
in vivo efficacy in tumor xenograft models and to progress to the
clinic.8 The initial promising clinical results9 with VX-680 sup-
ported the principle of targeting Aurora kinases for cancer therapy,
and led to the development of a host of other Aurora kinase inhib-
itors with varying levels of Aurora kinase A/B activity and selectiv-
ity. Selected examples of pan-Aurora inhibitors include PHA-
739358 (2),10 ENMD-2076 (3),11 AMG-900 (4).12 Aurora kinase A
specific inhibitors include MLN-8237 (5),13 and MK-5108 (6);14
Aurora kinase B specific inhibitors include AZD-1152 (7)15 and
GSK-1070916 (8)16 (Chart 1).
As the Aurora kinase isoform that is most critical for tumor pro-
gression is unknown, development of pan Aurora kinase inhibitors
were pursued mainly. In this article, we disclose the discovery of
novel, potent Aurora kinase inhibitors derived from a benzonap-
thyridinone scaffold (9). Aurora kinase inhibitors from this series
showed moderate cellular potency in anti-proliferative assays,
and modulated Aurora kinase B activity in vitro and in vivo.
A proprietary, kinase-focused library was screened in an effort
to identify novel Aurora kinase inhibitors. These efforts led to the
identification of 5H-benzo[c][1,8]naphthyridin-6-one (9) as an
⇑
Corresponding author. Tel.: +1 978 294 1432.
E-mail address: Srinivasa.karra@emdserono.com (S. Karra).
Current address: Ra Pharmaceuticals, Inc., One Kendall Square, Cambridge, MA
02139, United States.
à
Current address: Blueprint Medicines, 215 First Street, Cambridge, MA 02142,
United States.
§
Current address: SciFluor Life Sciences, 300 Technology Square, Cambridge, MA
02142, United States.
–
Current address: Pfizer Inc., 10770 Science Center Dr., San Diego, CA 92121,
United States.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.03.008

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S. Karra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3081–3087
H
N
N
O
N
HN
N
HN
N
N
H
H
O
MeO
N
N
O
N
N
S
N
N
2 (PHA-739358)
1 (VX-680)
H2N
N
S
N
N
N
O
N
N
N
HN
N
N
H
N
N
H
N
4 (AMG-900)
3 (ENMD-2076)
F
Cl
F
Cl
O
H
COOH
N
N
O
N
O
N
S
N
O
OH
N
N
H
5 (MLN-8237)
6 (MK-5108)
F
HN
N
O
N
O
NH
N
OH
OH
N
O
N
N
P
H
HN
N
O
N
N
N
H
N
O
8 (GSK-1070916)
7 (AZD-1152)
Chart 1. Structures of known Aurora kinase inhibitors.
initial hit. Compound 9 is a ligand-efficient fragment (LE = 0.45 k-
cal/mol/atom) that modestly inhibited Aurora kinase A with an
IC50 value of 5.5 lM. Despite its low affinity, compound 9 appeared
to be an attractive starting point for optimization due to its high
the backbone atoms of Ala213 of the kinase hinge region, and that
the kinase was in that active (DFG-in) conformation. The tricyclic
ring system of 9 interacts with the residues of the hydrophobic
adenine-binding pocket (Leu263, Leu139, Gly140 and Thr217)
(Fig. 1A and B). This binding mode of 9 clearly indicated that elab-
oration at position 1 of the scaffold could access the DFG loop, and
an opportunity to pass the gatekeeper residue (Leu 210) and access
the selectivity pocket for improved potency and kinase selectivity.
This hypothesis was tested via modification of the benzonap-
thyridinone scaffold at position 1 of 9. The benzonapthyridinone
analog 12 with a readily modifiable 1-position chloro moiety was
prepared by coupling 2-amino-3-iodo-4-chloro pyridine (10) with
boronic acid 11 using S-phos ligand and Pd(OAc)2, followed by ring
closure. This chloro intermediate 12, then underwent Pd-catalyzed
aminations with substituted anilines to yield analogs 13–16
(Scheme 1).
ligand efficiency.
1
C
6
A
N
B
N
H
O
4
9
5H-Benzo[c][1,8]naphthyridin-6-one
Aurora A IC50: 5540 nM
Molecular interactions of 9 with Aurora kinase A were deter-
mined via X-ray crystallography (PDB code: 4JAJ). The unambigu-
ous electron density maps indicated that two nitrogen atoms of
the inhibitor participate in the hydrogen-binding interactions with
Introduction of aniline (14) resulted in a fivefold increase in
inhibitory activity compared to inhibitor 9 (Table 1). Moderate in-
crease in potency against Aurora kinases A and B was observed
upon introduction of di-aminophenyl groups (16) (Table 1). Based

S. Karra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3081–3087
3083
Figure 1. X-ray structure of benzonapthyridinone scaffold (9) bound to Aurora kinase A. (A) Binding mode of inhibitor 9 in the ATP-binding site of Aurora kinase. Inhibitor is
shown in stick with the following atom colors: carbon-brown; nitrogen-blue; oxygen-red (drawn using PyMol program). (B) A schematic representation of inhibitor 9/Aurora
interactions drawn using MOE program.
R
Cl
N
Cl
b
NH
I
a
HO
HO
B
+
N
H
O
N
NH2
O
OEt
N
N
H
O
10
12
11
13-16
Scheme 1. Reagents and conditions: (a) Pd(OAc)2, S-Phos, K2CO3, Dioxane/H2O, 100 °C; (b) Pd(OAc)2, X-Phos, K2CO3, Dioxane/H2O, 100 °C.
Table 1
SAR of 1 position of 5H benzo [c][1,8]naphthyridin-6-one analogs
R
N
N
H
O
Compound
R
Aurora kinase A IC50 (nM)
Aurora kinase B IC50 (nM)
9
12
13
H
Cl
NH2
5540
3010
3010
NT
1440
NT
14
15
1030
1150
NT
N
H
H2N
174
N
H
H
N
16
471
NT
1
N
H
H
N
17
4
O
N
H
NT = not tested.

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S. Karra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3081–3087
into the hydrophobic pocket formed by residues Leu208, Leu196,
Phe275 and induces a partial DFG-out conformation in the pro-
tein (Fig. 2).
Further evaluation of compound 17 revealed that it displays
good selectivity for Aurora kinases over off-target kinases (Table 2),
moderate cellular potency (MIA PaCa-2 IC50: 329 nM), and poor
solubility (<1 lM). To further improve in vitro cellular potency
and physical properties, SAR efforts were focused on the optimiza-
tion of different regions of compound 17.
Replacement of D-ring with pyridine and pyrimidine rings re-
sulted in compounds (19–21). These were synthesized by coupling
12 with the corresponding amino-benzamides (Scheme 3). These
analogs were less potent against both Aurora kinases A and B than
the corresponding phenyl analog (17) (Table 3).
The terminal E-ring extends into the leucine rich hydrophobic
pocket, which seemed suitable to accommodate lipophilic substi-
tutions on the E-ring. Parallel to aforementioned D-ring investiga-
tions, we also probed the SAR around the terminal benzamide ring
(E) by incorporating lipophilic substituents. Compounds 27–43
were synthesized via the substitution of chlorine of in 12 with
the appropriate aminophenyl benzamides (26) using either Buch-
wald’s Pd-catalyzed amination conditions or nucleophilic aromatic
substitutions under acidic conditions (Scheme 4). The aminophe-
nyl benzamide intermediates (26) in turn were prepared by
H
N
H2N
NH
N
O
NH
N
b
N
H
O
N
H
O
17
15
Scheme 2. Reagents: (a) C6H6COOH, BOP-Cl, DIEA, DMF.
on molecular modeling studies of substituted anilines (15, 16), it
was hypothesized that further extension at the para position of
the aniline could further improve potency and reach the selectivity
pocket of the DFG-out confirmation.
As such, compound 17 was synthesized to explore this hypoth-
esis by coupling benzoic acid to the aniline 15 (Scheme 2). In vi-
tro results of compound 17 indeed showed potent inhibition of
both Aurora kinases A and B with IC50 values of 4 nM and
1 nM, respectively. The hypothesis was further confirmed via X-
ray crystallography of compound 17 with Aurora kinase A (PDB
code: 4JAI) which revealed that the carbonyl of the benzamide
group interacts with Lys162, while the distal phenyl ring extends
Figure 2. X-ray structure of inhibitor 17 bound to Aurora kinase A (A) Binding mode of compound 17. Inhibitor is shown in stick with the following atom colors: carbon-
yellow; nitrogen-blue; oxygen-red. (B) A schematic representation of compound 17/Aurora interactions.
Table 2
Off-target kinase selectivity profile of 17
Kinase
Ret
15
LIMK1
36
CHK2
41
ACK1
149
FGFR1
175
SIK
WNK3
401
SAPK4
411
Flt4
417
TrkA
819
Hck
958
IC50 (nM)
211
H
N
Y
Cl
N
Z
HN
O
O
X
+
a
NH
N
X
Y
Z
N
H
O
NH2
N
H
O
12
18a X = Z = CH, Y = N
18b X=Y= CH; Z= N
18c X=Y= N, Z = CH
19 X = Z = CH, Y = N
20 X=Y= CH; Z= N
21 X=Y= N, Z = CH
Scheme 3. Reagents and conditions: (a) Pd(OAc)2, X-Phos, NaO-tBu, Dioxane, 100 °C.

S. Karra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3081–3087
3085
Table 3
SAR of D-ring of 5H benzo[c][1,8]naphthyridin-6-one analogs
E
O
HN
D
NH
C
B
A
N
N
O
H
Compound
D
Aurora kinase A IC50 (nM)
4
Aurora kinase B IC50 (nM)
17
1
N
N
19
20
21
70
13
79
21
N
615
88
N
R
O
H
N
NHBoc
NH2
R1
b, c
+
R
a
O
H2N
NH2
H2N
24 R1 = Cl
25 R1 = OH
26
23
22
R
R
H
N
O
Cl
O
NH
N
d
NH
+
N
N
H
O
H2N
N
H
O
26
12
27-43
Scheme 4. Reagents and conditions: (a) Boc-anhydride, TEA, (b) 24, TEA, DCM or 25, BOP-Cl, DIEA (c) TFA, DCM; (d) Pd(OAc)2, X-Phos, K2CO3, Dioxane/H2O, 100 °C or Ethyreal
HCl.
coupling the Boc-protected 1,4-dianilines (23) with either an acid
chloride (24) or a carboxylic acid (25).
showed potent inhibition of pHH3 which correlates with observed
anti-proliferative potencies (Table 5).
Introduction of lipophilic substituents including 2-CF3 (29), 3-F
(30), and 4-F (32) on the E-ring maintained the cellular potency
(Table 4). To further improve the cellular potency, a number of
disubstituted E-ring analogs containing fluoro and trifluoromethyl
groups were prepared. Among these analogs, compound 39 inhib-
ited both Aurora kinases A and B with sub-nanomolar enzymatic
IC50 values of 0.3 and 0.4 nM, respectively and a concomitant in-
crease of anti-proliferative effects against the pancreatic cell line
(MIAPaCa-2 IC50 = 170 nM).
Incubation of MIA PaCa-2 cells with compound 39 for 24 h led
to an accumulation of cells with >4 N DNA content, which indicates
induction of endoreduplication, and is a phenotype consistent with
Aurora kinase B inhibition (Fig. 3).
Compound 39 was evaluated in a large panel kinase selectivity
screen (260 kinases tested @ 1 lM). The results indicate that com-
pound 39 possesses excellent off-target kinase selectivity as only 7
kinases other than the Aurora kinases are inhibited with an IC50
values less than 1 lM (Table 6).
Compounds 17 and 39 were tested for their ability to modulate
Aurora kinase B activity in cells by measuring the phosphorylation
of histone H3, a direct substrate of Aurora kinase B. Both analogs
Compound 39 was further evaluated in vivo by determining its
pharmacokinetic properties after intravenous administration to
mice at 5 mg/kg. Compound 39 exhibited medium clearance

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S. Karra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3081–3087
Table 4
SAR of terminal phenyl ring E
R
3
4
2
E
O
5
6
HN
D
NH
C
B
A
N
N
O
H
Compound
R
Aurora kinase A IC50 (nM)
Aurora kinase B IC50 (nM)
MIAPaCa-2 IC50 (nM)
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
2-OMe
2-F
2-CF3
3-F
4-CH3
7
9
4
7
3
4
27
2
2
5
7
7
0.3
7
9
9
3
2
2
1
1
2
1
6
0.5
1
0.6
0.8
0.7
0.4
1
NT
NT
1
2220
6250
405
919
2390
719
2710
209
374
293
409
823
170
253
4990
211
4-F
4-CF3
2,3-di-F
2,4-di-F
2,6-di-F
4,5-di-F
3,5-di-F
2-CF3, 4-F
2-F, 3-CF3
2-F, 4-CF3
3-F, 5-CF3
2-OMe, 6-F
1190
Table 5
Aurora kinase B target modulation
Compound
Aurora kinase B IC50 (nM)
MIAPaCa-2 IC50 (nM)
pHH3 inhibition (MIAPaCa-2) IC50 (nM)
17
39
1
0.4
329
170
208
52
MIA PaCa-2
DMSO
Compound 39
>4N
Fluorescenceunits
Figure 3. Induction of endoreduplication in MiaPaca-2 cells treated with compound 39.
equivalent to ꢀ31% of the liver blood flow in mice, which in turn
contributed to medium exposure (AUC: 4188 h ng/ml) and plasma
concentration (3930 ng/ml) of 39. Favorable plasma concentration
(Cmax: 321 ng/ml), exposure (AUC: 1442 h ng/ml), and moderate
bioavailability (F: 41%) of compound 39 were observed upon oral
administration at 5 mg/kg (Table 7).
was collected from the femurs of mice 2 h post-oral dosing of the
compound at 150 and 300 mg/kg. Both doses of compound 39 de-
creased histone H3 phosphorylation by 40–50%.
In summary, novel 5H-benzo[c][1,8]naphthyridin-6-one ana-
logs were developed as potent Aurora kinase inhibitors. Compound
17 and other analogs of this series bound to Aurora kinase A in the
partial DFG-out conformation and also exhibited higher kinase
selectivity. Among the several benzonapthyridinone analogs,
Compound 39 was tested in vivo for its ability to modulate Aur-
ora kinase B in mouse bone marrow (in Fig. 4). Total bone marrow

S. Karra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3081–3087
3087
Table 6
Regional Collaborative Access Team (SER-CAT) 22-ID beamline at
the Advanced Photon Source, Argonne National Laboratory.
Off-target kinase selectivity profile of 39
Kinase
Limk1
18
Chk2
161
Fms
575
Ret
Arg
863
Flt4
867
Blk
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Acknowledgments
We thank Dr. Igor Mochalkin for critical review of the manu-
script and many fruitful discussions, and Richard Walter and Gina
Ranieri for X-ray data collection. Data were collected at Southeast