Discovery and selectivity-profiling of 4-benzylamino 1-aza-9-oxafluorene derivatives as lead structures for IGF-1R inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.10.004

Recently the insuline-like growth factor receptor (IGF-1R) emerged as a promising target structure for the development of novel anti-cancer agents. IGF-1R plays a central role in both tumour progression and resistance development against anti-cancer drugs. We discovered 1-aza-9-oxafluorene derivatives as novel lead structures with submicromolar activities against IGF-1R. Structure-activity relationships (SARs) on a series of related receptor tyrosine kinases (RTKs) are discussed in the context of available crystal structures. A preliminary selectivity-profiling is demonstrated for the first compound series. Antiproliferative tumour cell line screening studies yielded one candidate as a promising cytostatic agent without significant toxic effects.

Full text of DOI:10.1016/j.bmcl.2010.10.004

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6915–6919
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and selectivity-profiling of 4-benzylamino 1-aza-9-oxafluorene
derivatives as lead structures for IGF-1R inhibitors
Martin Krug a, German Erlenkamp a, Wolfgang Sippl a, Christoph Schächtele b, Frank Totzke b,
Andreas Hilgeroth a,
⇑
a Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany
b ProQinase GmbH, Breisacher Straße 117, 79106 Freiburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Recently the insuline-like growth factor receptor (IGF-1R) emerged as a promising target structure for the
development of novel anti-cancer agents. IGF-1R plays a central role in both tumour progression and
resistance development against anti-cancer drugs. We discovered 1-aza-9-oxafluorene derivatives as
novel lead structures with submicromolar activities against IGF-1R. Structure–activity relationships
(SARs) on a series of related receptor tyrosine kinases (RTKs) are discussed in the context of available
crystal structures. A preliminary selectivity-profiling is demonstrated for the first compound series. Anti-
proliferative tumour cell line screening studies yielded one candidate as a promising cytostatic agent
without significant toxic effects.
Received 28 May 2010
Revised 30 September 2010
Accepted 1 October 2010
Available online 27 October 2010
Keywords:
Drug discovery
Inhibitors
Structure–activity relationships
Growth factor
Receptor
Ó 2010 Elsevier Ltd. All rights reserved.
The resistance development in cancer treatment emerged to a
central problem in the therapy with established cytostatics.1–3 Also
novel anti-cancer compounds like tyrosine kinase (TK) inhibitors
are affected by the resistance phenomenon. Lowered sensitivities
which are partly caused by mutations of amino acids in the ATP
binding pocket are reported in the case of clinically used inhibitors
of the epidermal growth factor receptor (EGFR).4,5 Another impor-
tant feature in the resistance development of TK inhibitors is the
heterodimerization of EGFR with the kinase insuline-like growth
factor receptor (IGF-1R).6–9 This kinase is overexpressed in many
cancer tissues.10,11 The overexpression leads to an enhanced cell
proliferation and tumour growth. Additionally, inhibition of cancer
cell apoptosis is influenced by IGF-1R, so that resistance develop-
ment against radiation therapy is also enforced by this kinase.10
IRF-1R emerged as a promising target for the therapy of cancer
and cancer resistance. We discovered 4-benzylamino 1-aza-9-oxa-
fluorene 1 as novel lead structure for IGF-1R inhibitors (Fig. 1).
Structure–activity relationships (SARs) on related receptor tyrosine
kinases (RTKs) are discussed based on enzyme inhibition data as
well as on available kinase crystal structures. Docking studies
using the EGFR, IGF-1R and VEGFR2 crystal structures were carried
out to rationalise the obtained biological data. First selectivity-
profiling data and antiproliferative activities are reported.
R
HN
R
HO
N
N
O
O
1, R = 4-OCH3, 3-Cl
2, R = COR´, OAlkyl
R
n
HN
N
O
3, n = 1, 2
R = Naph, Ph, subst. Ph
Figure 1. 1-Aza-9-oxafluorene lead structure 1, cycline dependent kinase inhibiting
1-aza-9-oxafluorene 2 and substituted 4-arylalkylamino template structure 3 of the
presented synthesised series.
First 1-aza-9-oxafluorenes 2 having a substituent in the 3-posi-
tion of the aromatic scaffold and a 6-hydroxy function were
reported to show cycline dependent kinase (CDK) inhibiting
⇑
Corresponding author. Tel.: +49 345 55 25168; fax: +49 345 55 27207.
E-mail address: andreas.hilgeroth@pharmazie.uni-halle.de (A. Hilgeroth).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.004

6916
M. Krug et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6915–6919
activity depending on the nature of the 3-substituent.12,13 An acyl-
ation of the 6-hydroxy function led to a loss of activity.12 The pres-
ence of a 4-aryl substituent was found to be important for CDK
activity.12
using sodium nitrite in sulphuric acid and a consequent ring clo-
sure using copper as catalyst. The N-oxide 916 was given by an oxi-
dation of compound 8 with meta chloroperbenzoic acid. The
reaction of the N-oxide 9 with phosphoroxychloride led to the 4-
chloro-1-aza-9-oxafluorene 1017 as template for the following
amine derivatization reactions. The different arylalkylamino com-
pounds 11a–g were given by boiling a mixture of the respective
amine and the 4-chloro-1-aza-9-oxafluorene 10.18 All novel com-
pounds were characterised by IR, 1H and 13C NMR spectroscopy,
mass spectrometry and elemental analysis.
We further varied the substitution pattern of the promising
1-aza-9-oxafluorene scaffold. First, we eliminated the 6-hydroxy
function to reduce the CDK inhibiting activity. Additionally, the
3-substituent was removed. Instead of the 4-aryl substituent we
introduced a 4-arylalkylamino function into the template structure
3. In this way the important aryl function in the 4-position was
maintained. In addition, the aryl function was enlarged by an
amino alkylene group. The amino function was introduced as a po-
tential hydrogen bond donor or acceptor function, respectively.
The synthesis of the 1-aza-9-oxafluorene scaffold started from
2-chloro-3-nitropyridine 4 which was treated with phenolate
anion (generated from phenole under proton abstraction with
sodium hydride) (Scheme 1).14
First screening results derived from a panel of RTKs showed that
some of the compounds show a preference for IGF-1R, EGFR and
VEGFR2. For example, the 4-benzylamino derivative 11a showed
submicromolar activity in the inhibition of IGF-1R, EGFR and of
the vascular endothelian growth factor 2 (VEGFR2) (Table 1).
The simultaneous inhibition of these kinases is attractive for the
treatment of cancer with overexpressing EGFR and VEGFR2 in the
late state of metastasis because both kinases are involved in en-
hanced cell viability, cell adhesion and invasion processes beside
their role in angiogenesis.19–24 An elongation of the alkyl side chain
by just one methylene function (compound 11b) led to a decrease
in activity of the RTK inhibition. Since the size of a hydrophobic
pocket near the gatekeeper residue, which is predicted by the
docking studies to be the binding site of the 4-aminobenzyl group,
is restricted in several kinases, the elongation of this group is unfa-
vourable.25 The naphthyl substituent in compound 11c is more
bulky than the phenyl substituent in compound 11a but was found
to adopt a similar location in the binding pocket as observed for the
phenyl ring. The activity data of compound 11c are similar to those
of the benzylamine derivative 11a. An interesting change in activ-
ity was observed for the 4-methoxyphenyl derivative 11d. Good
activities for the inhibition of IGF-1R and EGFR were found for
compound 11d while no inhibition of both VEGFR2 and VEGFR3
was observed. Derivative 11d represents a dual inhibitor of both
IGF-1R and EGFR and thus is indicated as a novel RTK inhibitor in
EGFR overexpressing cells. The combination of IGF-1R with EGFR
as addressed inhibitor target structures will mainly lower a resis-
tance development against the EGFR inhibition ability by prevent-
ing the effect of a heterodimerization because an IGF-1R/EGFR
heterodimer will also be inhibited by the dual inhibitor 11d.6,7,9
The 3-chloro derivative 11e exclusively inhibited IGF-1R and
thus is indicated in combination with established EGFR inhibitors
to lower the occurring resistance effect caused by heterodimeriza-
tion of both kinases. The 4-chloro derivative 11f was found as a
multikinase inhibitor with highest affinity for the investigated
RTKs within this first series. The inhibition of VEGFR3 is of worth
also because of the role of VEGFR3 in lymphatic angiogenesis.26
Finally, a pyridine ring was used as terminal aromatic system of
the 4-benzylamino group. No activity was found for the resulting
3-pyridyl derivative 11g.
The resulting 2-phenoxy-3-nitropyridine 5 was reduced to the
amino derivative 6 using hydrogen and palladium on charcoal as
catalyst.14 The cyclisation reaction of 6 to the 1-aza-9-oxafluorene
815 started with the formation of a diazonium salt intermediate 7
NO2
Cl
NO2
OPh
NH2
a
b
N
N
N
OPh
4
6
5
-
HSO4
+
N2
c
d
O
N
OPh
N
8
7
Cl
N
e
f
O
N
O
O
9
10
Comp.
R
_____________________
R
HN
N
a
b
c
d
e
f
Bn
Table 1
g
PhEt
Biological activity data for the 4-arylalkylamino substituted target compounds 11a–g
O
Naph-1-Me
4-MeOBn
3-ClBn
Compound
Ki valuesa,b
EGFR
(lM)
IGF-1R
VEGFR2
VEGFR3
11a-g
11a
11b
11c
11d
11e
11f
0.37
2.11
0.57
0.15
0.58
0.11
nac
0.59
3.45
0.68
0.40
nac
0.47
2.01
0.30
nac
1.09
9.39
1.09
nac
4-ClBn
nac
nac
g
3-Pyr-Me
0.50
0.18
0.68
11g
nac
nac
nac
Scheme 1. Reagents and conditions for compounds 4–11a–g: (a) PhOH, NaH,
toluene, reflux, 3.5 h (100%); (b) H2/Pd/C, ethyl acetate, rt (98%); (c) NaNO2, H2SO4,
0 °C; (d) Cu, H2SO4, 0 °C up to 55 °C, 90 min (31%); (e) m-chloroperbenzoic acid,
CHCl3, reflux, 8 h (100%); (f) phosphoroxychloride, CHCl3, 100 °C, 3.5 h (79%);
(g) arylalkylamine, 135–145 °C (51%—a, 62%—b, 60%—c, 61%—d, 42%—e, 51%—f,
65%—g).
a
Ki values have been calculated from determined IC50 values of RTK inhibition
following described protocols.12,13
b
Standard errors are typically below 20%. In many cases standard errors below
10% are found.
c
Inactive, Ki >1000 lM.

M. Krug et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6915–6919
6917
In order to provide a potential rationalisation for the detected
in vitro activities docking studies were carried out using the avail-
able crystal structures of human IGF-1R, EGFR and VEGFR2 in the
active form (PDB code 2zm3, 2ity, and 2p2h, respectively). All three
kinases have been crystallized with inhibitors addressing the
active form of the kinases. The inhibitors were docked into the
ATP binding pocket using the program GOLD (Cambridge Crystallo-
graphic Data Centre, Cambridge, UK) and default docking settings.
When docked to the three kinases, the 1-aza-9-oxafluorene ring
system is mimicking the adenine ring of ATP and represents a
hinge-binding motif. The inhibitors show a hydrogen bond be-
tween the pyridine nitrogen and the backbone NH of the hinge res-
idue Met793 (EGFR), Met1082 (IGF-1R) and Cys919 (VEGFR2),
respectively (Fig. 2a–c). The 4-benzylamino substituent is located
in a hydrophobic pocket nearby the gatekeeper residue (Thr790
in EGFR, Met1079 in IGF-1R and Thr916 in VEGFR2). The varying
gatekeeper residue and the size of the pocket are mainly responsi-
Figure 2c. GOLD docking results for EGFR. The docking study shows that in case of
the most active inhibitors 11d (coloured orange) and 11f (coloured dark yellow) the
4-benzylamino group is interacting with the gatekeeper pocket whereas for 11e
(coloured green) the substituted aromatic ring is pushed away from Met766.
ble for the observed selectivity of some inhibitors. In general,
hydrophobic substituents are favoured in this pocket and polar
groups (as in 11g) tend to stick out of this pocket resulting in inac-
tive derivatives. IGF-1R contains the more hydrophobic methio-
nine as gatekeeper residue (threonine in EGFR and VEGFR2)
resulting in higher affinities of the inhibitors possessing hydropho-
bic substituents at the 4-benzylamino group (11e, 11f).
Due to the larger hydrophobic pocket in IGF-1R (Fig. 2a) this
kinase accepts all 1-aza-9-oxafluorene derivatives, whereas in
the EGFR and VEGFR2 crystal structure the corresponding pocket
is smaller. As a result, the docking of 11d and 11e in VEGFR2
showed, that the substituted 4-benzylamino ring cannot be fully
buried in this hydrophobic pocket (Fig. 2b) resulting in a loss of
the hydrogen bond between pyridine nitrogen and the hinge
region (Cys919). A similar effect was observed for 11e at EGFR
(Fig. 2c). Also here, the size of the pocket nearby the gatekeeper
is responsible for a slightly different orientation of 11e compared
to the other inhibitors. As a consequence the distance of the impor-
tant hydrogen bond to the hinge region (Met793) is increased. In
general, a good agreement between the docking results and the
biological activities at IGF-1R, EGFR and VEGFR2 was observed.
The most potent IGF-1R/EGFR inhibitor 11d has been prelimi-
narily screened against 27 kinases from almost all families of the
human kinome. This was done to widely estimate the potential
of being well-tolerated in an anti-cancer therapy because of a
selective protein kinase inhibiting activity. To the best of our
knowledge, no selective IGF-1R inhibitor has been reported so
far.10,27,28
Figure 2a. GOLD docking results for IGF-1R. The two potent inhibitors 11d (coloured
green) and 11f (coloured orange) show favourable interaction between the
substituted 4-benzylamino group and the hydrophobic pocket nearby the gate-
keeper residue (Met1079). The hydrogen bond to the hinge region (Met1082) is
shown as dashed line.
The biological activities from the kinase panel are shown in
Table 2. All determined activity data range from 100
lM to
1000 M. This is a concentration range of practically no activity.
l
Complete loss of activity was found in the inhibition of 18 kinases.
It is noteworthy that no inhibitory activity was observed for
PDGFR-b and TIE2 because both are related kinases from the RTK
family. More interestingly we found an impressing selectivity in
the IGF-1R inhibition compared to the inhibition of the closely
related RTKs of both the InsR (insuline receptor) and the InsRR
(insuline receptor receptor) kinases which were practically not af-
fected by our inhibitor. So we found a first highly selective protein
kinase inhibitor as far as evaluated.
Figure 2b. GOLD docking results for VEGFR2. The potent inhibitor 11f (coloured
cyan) interacts with the hydrophobic pocket nearby the gatekeeper residue
(Thr916). For the two inactive derivatives 11d (coloured orange) and 11e (coloured
dark yellow) the docking shows that the substituted 4-benzylamino group cannot
be accomodated in this pocket. As a result the important hydrogen bond to the
hinge residue (Cys919) is lost.
The National Cancer Institute of Health (NCI) selected the mult-
ikinase inhibitor 11f for a tumour cell line screening. The antipro-

6918
M. Krug et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6915–6919
Table 2
ther derivatizations guided by the docking results are ongoing to
increase the affinity of the inhibitors.
Selectivity profile from the screening of protein kinase inhibition for compound 11d
Kinase familya
Kinase
IC50 valueb
M)
(
l
Acknowledgement
Tyrosine kinase (TK) family
ABL1
ABL2
FAK
InsR
InsRR
PDGFR-b
TIE2
392
nac
194
622
182
nac
nac
nac
759
376
129
nac
nac
nac
nac
nac
nac
nac
nac
nac
nac
nac
nac
129
nac
nac
271
The authors gratefully acknowledge the support of their work
by the country Saxoni-Anhalt and the Studienstiftung des Deuts-
chen Volkes to Martin Krug.
Receptor tyrosine kinase (RTK) family
References and notes
Tyrosine kinase like (TKl) family
IRAK1
LIMK1
CDK4/D1
CDK6/D1
CDK5/p25
CLK1
DYRK1A
HIPK1
Aurora A
Auroara C
1. Gardner, S. N.; Fernandes, M. J. Exp. Ther. Oncol. 2004, 4, 9.
2. Blagosklonny, M. V. Nat. Rev. Cancer 2002, 2, 221.
3. Lage, H. Cell. Mol. Life Sci. 2008, 65, 3145.
Cyclin dependent kinase (CDK) family
4. Kobayashi, S.; Boggon, T.; Dayaram, T.; Jänne, P.; Kocher, O.; Meyerson, M.;
Johnson, B.; Eck, M.; Tenen, D.; Halmos, B. N. Engl. J. Med. 2005, 352, 786.
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M. Proc. Natl. Acad. Sci. 2007, 105, 2070.
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J.; Wakeling, A.; Korsmeyer, S. J.; Streuli, C. H. J. Biol. Chem. 2002, 277, 27643.
7. Chakravarti, A.; Loeffler, J. S.; Dyson, N. J. Cancer Res. 2002, 62, 200.
8. Barnes, C. J.; Ohshiro, K.; Rayala, S. K.; El-Naggar, A. K.; Kumar, R. Clin. Cancer
Res. 2007, 13, 4291.
9. Morgillo, F.; Woo, J. K.; Kim, E. S.; Hong, W. K.; Lee, H. Y. Cancer Res. 2006, 66,
10100.
10. Ryan, P. D.; Goss, P. E. Oncologist 2008, 13, 16.
11. Reinmuth, N.; Fan, F.; Liu, W.; Parikh, A. A.; Stoeltzing, O.; Jung, Y. D.; Bucana, C.
D.; Radinsky, R.; Gallick, G. E.; Ellis, L. M. Lab. Invest. 2002, 82, 1377.
12. Brachwitz, K.; Voigt, B.; Meijer, L.; Lozach, O.; Schächtele, C.; Molnár, J.;
Hilgeroth, A. J. Med. Chem. 2003, 46, 876.
CDK-like family
Protein kinase A (PKA) family
PKC-c
PKC-iota
ERK1
Mitogen activated protein kinase (MAPK) family
Casein kinase (CK) family
p38-a
INK1
CK1-
VRK1
WEE1
Nek3
PLK1
a1
Nek protein kinase family
Polo subfamily
13. Voigt, B.; Meijer, L.; Lozach, O.; Schächtele, C.; Totzke, F.; Hilgeroth, A. Bioorg.
Med. Chem. Lett. 2005, 15, 823.
14. Cocker, J. D.; Gregory G. I. German Patent 2,022,024, 1970; Chem. Abstr. 1970,
74, 141731.
a
b
c
Kinase families as reported in Ref. 32.
IC50 value determination followed recent protocols.12,13
15. Spectroscopical data of 1-aza-9-oxafluorene 8: mp 57–61 °C; 1H NMR (CDCl3)
d = 7.31 (dd, J = 7.7, 4.9 Hz, 1H), 7.36 (ddd, J = 8.3, 7.6, 0.9 Hz, 1H), 7.50 (ddd,
J = 8.3, 7.3, 1.7 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.92 (dd, J = 7.7, 0.5 Hz, 1H), 8.26
(dd, J = 7.6, 1.7 Hz, 1H), 8.43 (d, J = 4.9 Hz, 1H); m/z (ESI) 170 (M+H+).
16. Spectroscopical data of 1-aza-9-oxafluorene-N-oxide 9: mp 176–178 °C; 1H
NMR (CDCl3) d = 7.28 (dd, J = 7.7, 6.6 Hz, 1H), 7.45 (ddd, J = 8.2, 7.3, 0.8 Hz, 1H),
7.59 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H),
7.95 (dd, J = 8.2 Hz, 1H), 8.32 (d, J = 6.6 Hz, 1H); m/z (ESI) 186 (M+H+).
17. Spectroscopical data of 4-chloro-1-aza-9-oxafluorene 10: mp 78–79 °C; 1H
NMR (CDCl3) d = 7.32 (d, J = 5.4, 1H), 7.45 (ddd, J = 8.3, 7.4, 0.9 Hz, 1H), 7.59
(ddd, J = 8.3, 7.4, 1.3 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.32
(d, J = 5.4 Hz, 1H); m/z (ESI) 204 (M+H+).
Inactive, Ki >1000 lM.
Table 3
Anti-cancer screening data of 60 tumour cell lines as mean graph
midpoint (MG_MID) values for inhibitor 11f in comparison to used
cytostatics
Compound
MG_MID values
log GI50
log LC50
18. General procedure for the formation of the arylalkylamino target compounds
11a–g: compound 10 (0.25 g, 1 mmol) was dissolved in the respective amine
(25 mmol) and the mixture was heated at 135 °C for 20 h under argon
11f
À4.47
À4.41
À4.48
À4.85
À5.68
>À4.00
>À4.00
À4.04
À4.02
À5.60
Etoposide
Melphalan
Irinotecan
Cisplatin
atmosphere. Then the mixture was poured into
a saturated potassium
carbonate solution (25 mL) and ethyl acetate (50 mL) was added. After the
phase separation the water phase was extracted with ethyl acetate (25 mL) for
three times. The unified organic layers were dried over sodium sulphate,
filtered and the eluent was removed in vacuum. The resulting products were
each given by column chromatography over silica gel using mixtures of
cyclohexane and ethyl acetate. Characterising spectroscopical data of
representing selective derivatives: compound 11d: mp 148–154 °C; IR (KBr)
liferative activities were characterised as mean graph midpoint
values for a reduced cell proliferation shown as log GI50 value
and for the lethal toxicity as log LC50 value determined in a sulphur
rhodamine B cytotoxicity assay.29,30
The results are shown in Table 3 in comparison to NCI database
values for established cytostatic drugs used in anti-cancer
therapies.31
m
= 3319, 3058, 2995, 1604, 1584; 1H NMR (DMSO-d6) d = 3.09 (s, 3H), 4.56 (d,
J = 6.0 Hz, 2H), 6.49 (d, J = 5.9 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz,
2H), 7.37–7.48 (m, 3H), 7.63 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 5.9 Hz, 1H), 8.43 (d,
J = 7.5 Hz, 1H); 13C NMR (DMSO-d6) d = 45.8, 55.6, 100.6, 102.5, 111.4, 114.4
(2 Â C), 122.0, 122.8, 123.4, 126.3, 128.5 (2 Â C), 131.3, 147.4, 150.5, 152.2,
158.7, 164.4; m/z (EI) 304 (M+). Elemental Anal. Calcd (%) for C19H16N2O2: C,
74.98; H, 5.30; N, 9.20. Found: C, 74.65; H, 5.41; N, 8.83. Compound 11e: mp
240–243 °C; IR (KBr)
m
= 3308, 3059, 2868, 1604, 1583; 1H NMR (DMSO-d6)
d = 4.65 (d, J = 6.1 Hz, 2H), 6.49 (d, J = 5.9 Hz, 1H), 7.26–7.31 (m, 1H), 7.32–7.53
(m, 6H), 7.65 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 5.9 Hz, 1H), 8.44 (d, J = 7.1 Hz, 1H);
13C NMR (DMSO-d6) d = 45.8, 100.8, 102.4, 111.4, 122.1, 122.7, 123.4, 126.0,
126.5, 127.1, 127.3, 130.8, 133.6, 142.3, 147.5, 150.3, 152.3, 164.4; m/z (EI) 308
(M+); Elemental Analy. Calcd (%) for C18H13ClN2O: C, 70.02; H, 4.24; Cl, 11.48;
N, 9.07. Found: C, 70.11; H, 4.01; Cl, 11.53; N, 8.87.
The antiproliferative activities as log GI50 values prove our
inhibitor 11f as active as etoposide, melphalan or irinotecan. Fur-
thermore, our compound showed the lowest toxicity in among
melphalan, irinotecan or cisplatin. Their higher toxicities are
known to be critical because such a general toxicity causes severe
side effects in anti-cancer therapy.
In the current work we discovered a new class of selective IGF-
1R inhibitors which are qualified for a cancer resistance therapy as
dual IGF-1R/EGFR inhibitors and as exclusive IGF-1R inhibitors for
an anti-cancer therapy with EGFR-resistant inhibitors. They are the
first reported small molecule IGF-1R inhibitors with a proved and
characterised selectivity profile. Moreover, they are suggested as
well-tolerated anti-cancer drugs showing no general toxicity and
an antiproliferative potential similar to clinically used drugs. Fur-
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27. Mayer, S. C.; Banker, A. L.; Boschelli, F.; Di, L.; Johnson, M.; Kenny, C. H.;
Krishnamurthy, G.; Kutterer, K.; Moy, F.; Petusky, S.; Ravi, M.; Tkach, D.; Tsou,
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