Pyrrolo[3,2-c]pyridine derivatives with potential inhibitory effect against FMS kinase: in vitro biological studies

Article abstract of DOI:10.1080/14756366.2018.1491563

A series of eighteen pyrrolo[3,2-c]pyridine derivatives were tested for inhibitory effect against FMS kinase. Compounds 1e and 1r were the most potent among all the other tested analogues (IC₅₀ = 60 nM and 30 nM, respectively). They were 1.6 and 3.2 times, respectively, more potent than our lead compound, KIST101029 (IC₅₀ = 96 nM). Compound 1r was tested over a panel of 40 kinases including FMS, and exerted selectivity against FMS kinase. It was further tested against bone marrow-derived macrophages (BMDM) and its IC₅₀ was 84 nM (2.32-fold more potent than KIST101029 (IC₅₀ = 195 nM)). Compound 1r was also tested for antiproliferative activity against a panel of six ovarian, two prostate, and five breast cancer cell lines, and its IC₅₀ values ranged from 0.15–1.78 μM. It possesses also the merit of selectivity towards cancer cells than normal fibroblasts.

Full text of DOI:10.1080/14756366.2018.1491563

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Pyrrolo[3,2-c]pyridine derivatives with potential
inhibitory effect against FMS kinase: in vitro
biological studies
Mohammed I. El-Gamal & Chang-Hyun Oh
To cite this article: Mohammed I. El-Gamal & Chang-Hyun Oh (2018) Pyrrolo[3,2-c]pyridine
derivatives with potential inhibitory effect against FMS kinase: inꢀvitro biological
studies, Journal of Enzyme Inhibition and Medicinal Chemistry, 33:1, 1160-1166, DOI:
10.1080/14756366.2018.1491563
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
2018, VOL. 33, NO. 1, 1160–1166
https://doi.org/10.1080/14756366.2018.1491563
RESEARCH PAPER
Pyrrolo[3,2-c]pyridine derivatives with potential inhibitory effect against FMS
kinase: in vitro biological studies
Mohammed I. El-Gamala,b,c
and Chang-Hyun Ohd,e
b
aDepartment of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates; Sharjah Institute for Medical
c
Research, University of Sharjah, Sharjah, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, University of
d
e
Mansoura, Mansoura, Egypt; Center for Biomaterials, Korea Institute of Science and Technology, Seoul, Republic of Korea; Department of
Biomolecular Science, University of Science and Technology, Daejeon, Republic of Korea
ABSTRACT
ARTICLE HISTORY
Received 26 April 2018
Revised 31 May 2018
Accepted 18 June 2018
A series of eighteen pyrrolo[3,2-c]pyridine derivatives were tested for inhibitory effect against FMS kinase.
Compounds 1e and 1r were the most potent among all the other tested analogues (IC50 ¼ 60 nM and
30 nM, respectively). They were 1.6 and 3.2 times, respectively, more potent than our lead compound,
KIST101029 (IC50 ¼ 96 nM). Compound 1r was tested over a panel of 40 kinases including FMS, and
exerted selectivity against FMS kinase. It was further tested against bone marrow-derived macrophages
(BMDM) and its IC50 was 84 nM (2.32-fold more potent than KIST101029 (IC50 ¼ 195nM)). Compound 1r
was also tested for antiproliferative activity against a panel of six ovarian, two prostate, and five breast
cancer cell lines, and its IC50 values ranged from 0.15–1.78 mM. It possesses also the merit of selectivity
towards cancer cells than normal fibroblasts.
KEYWORDS
CSF-1R; FMS; kinase
inhibition; pyr-
rolo[3,2-c]pyridine
Introduction
Experimental
Colony-stimulating factor-1 receptor (CSF-1R), or FMS, kinase is a Synthesis of the target molecules 1a–q
member of type III receptor tyrosine kinases family. It interacts
Compounds 1f, 1m–o, and 1q are new, while the other 12 com-
pounds are previously reported18–20. In addition, compound 1r is
also new. The synthetic procedure utilised for its synthesis as well
as its spectral data are reported in the next section. The synthetic
procedures, purification methods, and the spectral analysis data
for compounds 1a–q have been provided in the supplemen-
tary file.
with CSF-1 or Il-34, and the produced signal transduction results
in proliferation and survival of the monocyte/macrophage lineage
cells1,2. FMS kinase is over-expressed in different cancer types (e.g.
ovarian3, prostate4, and breast5–7) as well as inflammatory disor-
ders (e.g. rheumatoid arthritis)8. So FMS inhibitors could be useful
drug candidates for treatment of these disorders.
Several FMS kinase inhibitors of different chemical classes
have been recently reviewed by our group9. Among them, dia-
rylamide derivatives have been reported10–15. We have previ-
ously reported a diarylamide derivative (KIST101029, Figure 1)
as a potent and selective FMS kinase inhibitor16. It exerted also
high potency against ovarian, prostate, and breast cancer
cell lines17.
In the present study, we tested a series of diarylamides
and diarylureas possessing pyrrolo[3,2-c]pyridine scaffold against
FMS kinase. Many of them were previously reported as anti-
proliferative agents18–20. The most potent compound against
FMS kinase was tested against a panel of 40 kinases including
FMS, tested against a panel of 13 cancer cell lines of 3 differ-
ent cancer types and HS 27 fibroblasts, and against bone mar-
row-derived macrophages (BMDM) in order to investigate its
biological effects. The results were compared with those of the
lead compound KIST101029. The results, structure-activity rela-
tionship (SAR) studies, and relevant discussions are presented
in details.
Synthesis of compound 1r
A mixture of compound 8b (24 mg, 0.1 mmol), 4-morpholino-3-(tri-
fluoromethyl)benzoic acid (57 mg, 0.2 mmol), HOBt (31 mg,
0.22 mmol), and EDCI (50 mg, 0.26 mmol) in dry DMF (2.0 ml) was
cooled to 0 ꢀC in inert atmosphere. TEA (0.04 ml, 0.02 mmol) was
added thereto at the same temperature. The mixture was then
stirred at 80 ꢀC for 12 h. The reaction mixture was cooled and
then partitioned between water (10 ml) and ethyl acetate (15 ml),
and the organic layer was separated. The aqueous layer was then
extracted with ethyl acetate (2 ꢁ 10 ml) and the combined organic
phase was washed with brine and dried over anhydrous sodium
sulphate. The organic solvent was evaporated, and the residue
was purified by column chromatography (silica gel, hexane-ethyl
acetate 4:1 v/v followed by 1:1 v/v) to get the pure compound.
Yield 7.5%; 1H NMR (400 MHz, CDCl3): d 8.56 (s, 1H), 8.39 (s, 1H),
8.17–8.07 (m, 2H), 7.71–7.53 (m, 2H), 7.39 (brd, 2H, J ¼ 8.6 Hz), 7.34
(t, 1H, J ¼ 3.2 Hz), 7.30 (brd, 1H, J ¼ 8.0 Hz), 7.13 (brs, 2H), 6.83
CONTACT Chang-Hyun Oh
choh@kist.re.kr
Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650,
Republic of Korea
Supplemental data for this article can be accessed here.
ß 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1161
(brd, 1H, J ¼ 7.7 Hz), 6.74 (dd, 1H, J ¼ 1.9 Hz and 1.5 Hz), 3.86 (t, 4H, (30,000 cells/well) were cultured in RPMI 1640 medium containing
J ¼ 2.6 Hz), 3.02 (t, 4H, J ¼ 2.1 Hz); LC-MS: 482.1 (Mþ þ1), 481.1 10% foetal bovine serum, 2-mercaptoethanol (50 mM), and the
(Mþ); elemental analysis: Calculated: C: 62.36%, H: 4.61%, N: test compound for 1 h at 37 ꢀC in the presence of 5% CO2. CSF-1
14.55%, Found: C: 62.23%, H: 4.50%, N: 14.68%.
(20 ng/mL) was then added and the system was incubated for
5 days. Each compound was tested in a 10-dose testing mode,
threefold serial dilution starting with 1 mM concentration. The
inhibitory effects of the tested compounds against CSF-1-induced
BMDM growth were determined using Alamar BlueTM (Serotec).
Bioactivity protocol
In vitro kinase screening
Reaction Biology Corp. Kinase HotSpotSM service [http://www.reac-
tionbiology.com] was utilised for screening of the target com-
pounds as per the protocol reported in the literature21. In order to
calculate the IC50 values and the inhibition percentages at differ-
ent concentrations, each compound was tested in 10-dose dupli-
cate assay mode starting with 81 mM and threefold serial dilution.
Results and discussion
Chemistry
The 4-benzamidopyrrolo[3,2-c]pyridine derivatives 1a–k were syn-
thesised as per the pathway illustrated in Scheme 1. Pyrrolo[2,3-
b]pyridine (2) was treated with m-chloroperoxybenzoic acid to
produce the m-chlorobenzoate salt 3. Heating compound 3 with
phosphorus oxychloride yielded 4-chloropyrrolo[2,3-b]pyridine
(4)22. Fusion of compound 4 with the appropriate nitroaniline
yielded 1-aryl-4-aminopyrrolo[3,2-c]pyridine HCl salts (5a,b) after
ring rearrangement23. The amines 5a,b were treated with benzoyl
chloride in the presence of diisopropylamine to produce the cor-
responding benzamido analogues 6a,b. The nitro group of com-
pounds 6a,b was reduced using hydrogen gas and Pd/C to yield
the corresponding aniline derivatives 7a,b. In order to get the dia-
rylurea products 1a–e, compounds 7a,b were reacted with appro-
priate aryl isocyanate at room temperature. On the other hand,
heating the amines 7a,b with the appropriate benzoic acid deriva-
tive in the presence of EDCI, HOBt, and triethylamine led to con-
Antiproliferative screening against cancer cell lines
Compounds 1r and KIST101029 were tested at the National
Cancer Institute (NCI, Bethesda, MD) following their standard
protocol
[https://dtp.cancer.gov/discovery_development/nci-60/
methodology.htm].
Antiproliferative screening against HS 27 fibroblasts
It was conducted following the previously reported protocol17.
BMDM assay
The macrophages were isolated from C57BL6 murine bone mar-
row using Miltenyi Biotec MACS beads (CD11b). The macrophages
densation
reaction
and
formation
of
the
bisamide
products 1f–k18–20
.
O
Reaction of compounds 6a,b using stannous chloride refluxing
ethanol led to reduction of the nitro group and hydrolysis of the
benzamido moiety to yield the diamine derivatives 8a,b. The anil-
ine amino group is more reactive in the next reactions than the
other amino attached to the heterocyclic nucleus due to higher
electron density and higher nucleophilicity. Formation of the urea
products 1l,m and the amide derivatives 1n–r (Scheme 2) was car-
ried out by the same methods described for synthesis of com-
pounds 1a–e and 1f–k, respectively (Scheme 1).
N
CF3
H
N
H
N
O
N
O
N
Figure 1. Structure of the lead compound, KIST101029.
Cl
O
N
b
H2N
HCl
a
c
NO2
O
N
N
N
N
N
N
N
H
H
H
OH
Cl
5a,b
2
4
3
H
N
e
NO2
H
N
d
N
NH2
N
O
N
O
N
6a,b
7a,b
g
f
H
N
H
H
H
N
H
N
N
N
N
Ar
N
Ar
O
N
O
O
O
N
1f-k
1a-e
Scheme 1. Reagents and conditions: (a) 3-chloroperoxybenzoic acid, DME:heptane (1:2), rt, 2.5h; (b) POCl3, 55 ꢀC then rt then 85–90 ꢀC, 18h; (c) appropriate nitroani-
line, 180ꢀC, 2–5 h; (d) benzoyl chloride, diisopropylamine, CH3CN, rt, 8 h; (e) Pd/C, H2, THF, rt, 2 h; (f) aryl isocyanate, THF, rt, 8 h; (g) benzoic acid derivative, HOBt,
EDCI, TEA, DMF, 80 ꢀC, 12 h.

1162
M. I. EL-GAMAL AND C.-H. OH
O
Ar
H
NH2
N
N
N
N
NO2
H2N
H2N
N
b
a
N
H
H
N
O
N
N
1l,m
6a,b
8a,b
c
H
N
N
H2N
Ar
N
O
1n-r
Scheme 2. Reagents and conditions: (a) SnCl2.H2O, EtOH, reflux, 4 h; (b) aryl isocyanate, THF, rt, overnight; (c) benzoic acid derivative, HOBt, EDCI, TEA, DMF,
80 ꢀC, 12h.
Biology
Compound 1r was tested against a panel of 40 kinases includ-
ing FMS. The inhibition percentages at 1 mM concentration are
summarised in Table 2. It showed selectivity against FMS kinase
with 81% inhibition. Its inhibition percentages against FLT3
(D835Y) and c-MET kinases were 42% and 40%, respectively. So its
IC50 values against both of them will be in micromolar scale.
Compared with its IC50 values against FMS kinase (30 nM, Table 1),
it can be concluded that compound 1r is more than 33 times
more selective towards FMS than the other kinases. The inhibition
percentages exerted by compound 1r against the other 37 tested
kinases were less than 28%.
Kinase screening results and discussion
Compounds 1a–r were tested in a 10-dose testing mode starting
with 81 mM, threefold serial dilutions, against FMS kinase in a cell-
free enzyme assay. The IC50 values are summarised in Table 1.
Upon comparing the structures and potencies, it was found that
compounds 1c, 1e, and 1g possessing benzamido moiety at pos-
ition 4 of the pyrrolopyridine nucleus were more potent than the
corresponding primary amino analogues 1 l, 1m, and 1o. This can
be due to occupancy of a hydrophobic pocket with that add-
itional benzoyl moiety and/or formation of additional hydrogen
bond by the carbonyl oxygen. On the contrary, the amino ana-
logues 1p and 1r were more potent than the corresponding ben-
zamido derivatives 1j and KIST101029.
The central phenyl ring attached to N1 atom of the pyrrolopyri-
dine nucleus was para-disubstituted in some derivatives or meta-
disubstituted in others. The results showed that para-disubstituted
compounds 1a, 1c, and 1h were more potent than the corre-
sponding meta-disubstituted derivatives 1b, 1d, and 1i. On the
other hand, the meta-disubstituted compounds 1g, 1o, and 1r
showed stronger inhibitory effect against FMS kinase than the
para-disubstituted positional isomers 1f, 1n, and 1p. These differ-
ences in the substitution position can affect proper orientation
and fitting at the active site.
The urea derivatives 1a, 1b, 1e, and 1m were generally more
potent than the corresponding analogues with amide linker 1h,
1i, 1k, and 1q. The urea linker is longer and can be optimal for
best fitting at the binding site. The urea spacer contains also add-
itional NH, compared with the amide. This terminal NH could con-
tribute to stronger affinity by additional hydrogen bonding. Any
or both of these effects can account for stronger enzyme inhib-
ition effect of the urea derivatives.
Upon investigating the terminal aryl ring effect on the activity,
it was found that 30,50-bis(trifluoromethyl)phenyl and 40-morpho-
lino-30-(trifluoromethyl)phenyl are the best rings in diarylureas and
diarylamides, respectively. These rings may contribute to stronger
affinity with the enzyme. The morpholino moiety is also a polar
ring, which enhances the solvent exposure and aqueous solubility
of the molecule.
Cell-based biological assays of compounds 1r and KIST101029
Due to over-expression of FMS kinase in certain types of tumours
such as ovarian3, prostate4, and breast5–7 cancers, we decided to
test the antiproliferative activity of compound 1r against a panel
of six ovarian, two prostate, and five breast cancer cell lines. It
was also tested against HS 27 fibroblasts in order to investigate
the selectivity indexes. The results were compared with those of
KIST101029 as a reference standard. The IC50 values are pre-
sented in Table 3, and the dose-response curves of compound 1r
are shown in Figure 2.
At 10 mM concentration, compound 1r was more active than
KIST101029 against four ovarian, two prostate, and two breast
cancer cell lines (Supplementary file). 1r was also more potent
than KIST101029 against HS 578 T breast cancer cell line. TGI val-
ues reflect the efficacy of the molecule. Compound 1r was more
efficacious than KIST101029 against MCF7, MDA-MB-231/ATCC,
and HS 578 T breast cancer cell lines. But in general, KIST101029
was more potent than 1r against most of the tested cell lines. The
structural difference, benzamido in KIST101029 compared with
amino in 1r, is responsible for this potency difference. The benza-
mido moiety is more hydrophobic and is expected to allow
greater ability of the molecule to cross the cell membrane to
inside the cell. So the exposure of the intracellular components to
compound KIST101029 is expected to be higher. Furthermore,
the benzamido moiety may form additional interactions with the
receptor site, which can contribute to stronger affinity and
potency. However, the IC50 values of compound 1r were in the
range of 0.15–1.78 mM, which is an excellent range of potency. In
addition, compound 1r has another merit over KIST101029. Its
IC50 value against HS 27 fibroblasts was higher, i.e. greater select-
ivity towards cancer cells than normal cells. Upon dividing its IC50
value against HS 27 fibroblasts by IC50 range over cancer cells, we
find that the selectivity range of compound 1r ranges from 3.21
to 38.13 times towards cancer cells than normal cells.
Among all the tested compounds, 1e and 1r were more potent
than the lead compound KIST101029. Their potencies were 1.6
and 3.2 times, respectively, higher than that of KIST101029.
Compound 1r possessing primary amino, meta-disubstituted cen-
tral phenyl, amide linker, and 40-morpholino-30-(trifluoromethyl)-
phenyl terminal ring was the most potent among this series of
compounds. So we decided to consider it for further biological
investigations.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1163
Table 1. Structures of the target compounds and their IC50 values against FMS kinase.
H
N
R2
H
N
N
R1
O
N
Compound No.
R1
Bz
Site of attachment to benzene ring
R2
IC50 (lM)a
1a
para
0.19 0.02
N
N
N
N
H
H
H
H
CF3
CF3
1b
1c
1d
1e
1f
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
H
meta
para
meta
para
para
meta
para
meta
para
para
para
para
para
meta
1.43 0.29
0.39 0.02
2.47 0.03
0.06 0.01
>81
Cl
CF3
Cl
CF3
CF3
N
H
CF3
Cl
Cl
Cl
Cl
1g
1h
1i
1.27 0.07
10.80 0.60
>81
CF3
CF3
N
O
1j
33.15 0.45
>81
CF3
CF3
CF3
1k
1l
N
N
Cl
3.20 0.07
1.45 0.03
>81
H
CF3
CF3
1m
1n
1o
H
H
CF3
Cl
H
Cl
Cl
Cl
H
40.70 2.40
(continued)

1164
M. I. EL-GAMAL AND C.-H. OH
Table 1. Continued.
Compound No.
1p
R1
H
Site of attachment to benzene ring
R2
IC50 (lM)a
para
0.10 0.03
N
O
CF3
CF3
1q
H
H
para
>81
0.03 0.02
0.096
CF3
N
O
1r
meta
CF3
O
N
CF3
KIST101029
H
N
H
N
N
O
O
N
aIC50 values are expressed as means of 10-dose duplicate assay SEM.
Table 2. Inhibition percentages exerted by compounds 1r and KIST101029 over
40-kinase panel including FMS kinase.
Table 3. IC50 and TGI values in lM of compound 1r and KIST101029 over ovar-
ian, prostate, and breast cancer cell lines.
% Inhibitiona–c
5-dose results
Kinase enzyme
1r
KIST101029
of
5-dose results
of KIST101029
ABL1
ALK
15%
0%
41%
11%
21%
7%
ꢂ1%
ꢂ12%
8%
ꢂ8%
ꢂ16%
10%
ꢂ18%
1%
9%
6%
16%
90%
44%
4%
Compound 1r
a
a
Cell line
IGROV1
IC50
TGIb
IC50
TGIb
Aurora A
BTK
CaMKI
CDK2/cyclinE
CDK5/p25
CHK1
ꢂ2%
1%
Ovarian cancer
0.70
0.24
1.08
1.38
1.26
0.34
0.38
1.30
0.15
0.84
0.34
1.78
0.30
5.72
43.3
1.47
26.0
>50
9.96
>50
10.40
4.67
6.86
2.32
2.43
27.5
3.14
-
0.06
0.02
0.24
0.20
0.06
0.04
0.06
0.04
0.04
0.16
0.99
0.08
0.03
0.30
56.9
0.05
50.0
>100
>100
26.4
>100
0.10
54.0
3.42
97.2
7.46
0.10
-
ꢂ23%
ꢂ1%
ꢂ5%
ꢂ6%
40%
ꢂ4%
ꢂ1%
4%
ꢂ10%
ꢂ3%
42%
81%
14%
ꢂ3%
6%
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
PC-3
DU-145
MCF7
MDA-MB-231/ATCC
HS 578T
c-MET
c-SRC
Prostate cancer
Breast cancer
DMPK
EGFR (T790M)
EPHA1
FGFR1
FLT3 (D835Y)
FMS
FYN
GSK3b
HIPK2
T-47D
MDA-MB-468
HS-27 Fibroblasts
aIC50 is the concentration producing 50% inhibition. The results are expressed as
means of duplicate experiments.
9%
IGF-1R
IKKb
IR
4%
1%
5%
10%
23%
2%
bTGI is the concentration producing 100% inhibition.
JNK1a1
KDR
LCK
MEK1
MLK1
mTOR
P70S6K
PAK2
PDK1
PIM1
PLK1
RET
ROCK1
ROS/ROS1
RSK1
SAPK2a
SYK
ꢂ5%
ꢂ1%
71%
33%
12%
ꢂ1%
ꢂ10%
7%
1%
BMDM assay
ꢂ7%
ꢂ7%
ꢂ4%
ꢂ2%
ꢂ8%
ꢂ9%
ꢂ7%
ꢂ6%
7%
27%
2%
ꢂ4%
ꢂ4%
ꢂ1%
ꢂ5%
10%
FMS over-expression contributes to inflammatory disorders as
explained in the Introduction section. So compounds 1r and
KIST101029 were tested for their ability to inhibit CSF-1-induced
BMDM growth. The IC50 values are summarised in Table 4. The
more potent FMS kinase inhibitor 1r exerted 2.32-fold superior
potency than KIST101029 in this assay. So, the compound 1r can
be a promising candidate for future development of anti-arth-
ritic drugs.
2%
ꢂ1%
10%
4%
57%
3%
19%
8%
25%
6%
14%
Each compound was tested in a 10-dose testing mode, three-
fold serial dilution starting with 1 mM concentration.
TEC (activated)
Conclusions
aThe compounds were tested at a single-dose concentration of 1 lM.
b100% Activity refers to enzyme activity in negative control (DMSO).
c% Inhibition was calculated by subtracting % activity from 100.
Shade significe the most sensitive kinase.
Our previous report on the potent and selective FMS kinase
inhibitor, KIST101029, encouraged us to investigate the FMS kin-
ase inhibitory effects of analogues of that lead compound.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1165
Figure 2. Dose-response curves of compound 1r over the ovarian, prostate, and breast cancer subpanels.
2. Woolford J, Rothwell V, Rohrschneider L. Characterization of
the human c-fms gene product and its expression in cells of
the monocyte-macrophage lineage. Mol Cell Biol
1985;5:3458–66.
3. Kacinski BM, Carter D, Mittal K, et al. Ovarian adenocarcino-
mas express fms-complementary transcripts and fms anti-
Table 4. IC50 values of the tested compounds against bone marrow-derived
macrophages (BMDM).
Compound No.
IC50 (nM)a
1r
84
195
3
6
KIST101029
aIC50 values are expressed as means of triplicate assay SEM.
gen, often with coexpression of CSF-1. Am
J Pathol
1990;137:135–47.
Eighteen compounds were tested, and this study led to discovery
of compound 1r as a more potent and selective FMS kinase
inhibitor (3.2 times more potent than KIST101029). It showed
strong potency against the tested ovarian, prostate, and breast
cancer cell lines with IC50 values ranged from 0.15 to 1.78 mM. It
selectivity index towards cancer cells than normal fibroblasts
ranged from 3.21 to 38.13. In addition, compound 1r showed
potential anti-inflammatory effect against bone marrow-derived
macrophages. This compound is a promising candidate for anti-
cancer and anti-arthritic drug development. Further lead optimisa-
tion and biological investigations are required.
4. Zhu P, Baek SH, Bourk EM, et al. Macrophage/cancer cell
interactions mediate hormone resistance by a nuclear recep-
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Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by Korea Institute of Science and
Technology (KIST, Seoul, Republic of Korea), KIST Project (E26900).
ORCID
pite disease-modifying antirheumatic drug therapy.
Rheumatol 2015;42:1752–61.
J
Mohammed I. El-Gamal
http://orcid.org/0000-0002-4269-5264
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