Allosteric IGF-1R inhibitors

Article abstract of DOI:10.1021/ml100044h

Targeting allosteric protein sites is a promising approach to interfere selectively with cellular signaling cascades. We have discovered a novel class of allosteric insulin-like growth factor-I receptor (IGF-1R) inhibitors. 3-Cyano-1H-indole-7-carboxylic acid {1-[4-(5-cyano-1H-indol-3-yl)butyl] piperidin-4-yl}amide (10) was found with nanomolar biochemical, micromolar, cellular IGF-1R activity and no relevant interference with cellular insulin receptor signaling up to 30 ?M. The allosteric binding site was characterized by X-ray crystallographic studies, and the structural information was used to explain the unique mode of action of this new class of inhibitors.

Full text of DOI:10.1021/ml100044h

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Allosteric IGF-1R Inhibitors
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Timo Heinrich,* Ulrich Gradler, Henning Bottcher, Andree Blaukat, and Adam Shutes
†Merck Serono, Frankfurter Strasse 250, 64293 Darmstadt, Germany, and ‡EMD Serono Research Institute, One Technology
Place, Rockland, Massachusetts 02370
ABSTRACT Targeting allosteric protein sites is a promising approach to interfere
selectively with cellular signaling cascades. We have discovered a novel class of
allosteric insulin-like growth factor-I receptor (IGF-1R) inhibitors. 3-Cyano-1H-
indole-7-carboxylic acid {1-[4-(5-cyano-1H-indol-3-yl)butyl]piperidin-4-yl}amide
(10) was found with nanomolar biochemical, micromolar, cellular IGF-1R activity
and no relevant interference with cellular insulin receptor signaling up to 30 μM.
The allosteric binding site was characterized by X-ray crystallographic studies, and
the structural information was used to explain the unique mode of action of this
new class of inhibitors.
KEYWORDS IGF-1R, kinase inhibitor, allosteric inhibition, indole-butyl-amine
ong-term medical indications require long-term drug
treatments with a well-tolerated toxicity profile. This
has been understood for the treatments of conditions
progression of cancer patients and might provide a proof of
concept for this target.13-16
L
The insulin receptor (IR) is a related receptor tyrosine
kinase and shares a high sequence identity of 84% in the
tyrosine kinase domain with IGF-1R.17 This homology
makes it very difficult to target one of the receptors selec-
tively and means a special challenge for IGF-1R inhibitor
design.18 In this context, it is interesting that the overall
folding of the catalytic domains of protein kinases is very
similar in the fully activated form, while striking differences
exist among the various inactive conformations of different
kinase subfamilies.19,20
This is also true for IGF-1R and IR, which have been
structurallycharacterized in the unactivated, nonphosphory-
lated (0P), and fully activated, triply phosphorylated (3P)
forms.21,22 Overall, the structures of unactivated IGFR-0P
closely resemble those of the IR-0P, which is also true for the
fully active forms IGFR-3P and IR-3P. However, the unacti-
vated and activated forms are structurally very distinct from
each other, especially regarding the positions of the activa-
tion loop and RC helix.
In a high-throughput screening (HTS) campaign of the
Merck Serono compound collection against IGF-1R, com-
pound 1 was found to inhibit the enzyme (Figure 1). Although
the inhibitory activity with an IC50 of 10 μM was only
moderate, we decided to further characterize this hit.
Subsequent cellular testing in a phospho-IGF-1R enzyme-
linked immunosorbent assay (ELISA) revealed an IC50
value of 18 μM for 1.
such as high blood pressure and is now also realized even in
life-threatening diseases, such as cancer.1 Selectivity and
specificity of the corresponding drugs are therefore essen-
tial. Kinases are involved in numerous crucial cell-signaling
cascades and have been implicated in oncogenesis and
tumor progression through their aberrant regulation or over-
expression. Many drugs on the market or in clinical deve-
lopment inhibit kinases.2 Kinase inhibition by ATP com-
petition (type I) is associated with selectivity hurdles due to
the high sequence conservation in the ATP-binding pocket
within the kinome. However, the conformational variability
of kinases allows for allosteric inhibition by targeting non-
ATP sites (type II/III). Such allosteric binding sites are less
frequent in protein kinase structures through the kinome,
offering a very promising approach to achieve the selectivity
objective.3
There are only a few published reports of kinase inhibitors
that are non-ATP and/or substrate competitive. After the
initial identification of SB-203580, a specific inhibitor of
the serine/threonine kinase p38 MAPK (mitogen-activated
protein kinase),4 which interacts with amino acid residues
outside of the ATP binding pocket, additional compounds for
p38,5 PLK1,6 GSK-3,7 Akt,8 and MEK9 were reported, but
only for a few of them could the allosteric interaction be
demonstrated experimentally.
The insulin-like growth factor-I receptor (IGF-1R) is a
member of the receptor tyrosine kinase family.10 The pep-
tides IGF-1 and IGF-2 are the cognate activating ligands of
IGF-1R.11 Several lines of epidemiological and mechanistic
evidence link IGF-1R activation and signaling to tumor
biology.12 Recent reports of Pfizer's IGF-1R antibody CP-
751871 (currently in clinical trials) support the hypothesis
that IGF-1R inhibition has a beneficial effect on the disease
Structures from this indolealkylamine class are known to
bind to G-protein-coupled receptors in the central nervous
Received Date: February 25, 2010
Accepted Date: May 10, 2010
Published on Web Date: May 18, 2010
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Table 1. Biochemical and Cellular Activity of Indole-butyl-ami-
nesa
Figure 1. Structure of HTS hit 1.
system (CNS) with nanomolar affinity. They have been pre-
viously shown to be very selective binders of the serotonin
receptorsubtype 1A and the serotoninreuptake transporter,23
but it was not known before that, in addition to their CNS
activity, some of these compounds also inhibit protein kinases
such as IGF-1R.
The chemical structure of the screening hit 1 does not
obviously represent a typical hinge-binding motif.24 There-
fore, we started with structure-activity relationship (SAR)
expansion around this hit (Table 1).
Compounds1-12 were prepared as previouslydescribed.23
The synthesis of building block 15 starts with the acylation of
5-cyano-indole 13 with chloro butyric acid chloride, and after-
ward, the carbonyl carbon is completely reduced with a com-
plex aluminum hydride reagent to 14. The chlorine is sub-
stituted with 4-(BOC amino)piperidine under basic conditions,
the protecting group is cleaved with acid, and the free amine
15 is subjected to standard amide coupling conditions to give
the target compounds (Scheme 1).
A significant potency gain on IGF-1R by a factor of 4 was
observed by shifting the amide bond attachment on the
indole ring from position 6 (1, IC50 = 10 μM) into position 7
(2, IC50 = 2.5 μM). In line with this trend, although less
pronounced, was the 4-indolyl derivative 3 (IC50 = 6.0 μM),
indicating a certain influence of the angular attachment of
the amide to the indole ring. Hence, we focused on 4- and
7-yl indoles bearing electron-withdrawing and -donating
substituents to further explore the SAR. As summarized in
Table 1, slight modifications have a dramatic impact on the
compounds' potency. The attachment of electron-donating
substituents such as methyl (4, IC50 = 2.7 μM) and ethyl
(5, IC50 = 3.6 μM) on the 4-indolyl nitrogen resulted in a
distinct reduction of inhibition as compared to the unsub-
stituted indole 3. The decrease in potency was also observed
in a subseries of 7-indolyl derivatives with carbonyl substitu-
tion in the 3-position. In comparison with the unsubstituted
derivative 2, a 2-3-fold drop of potency was observed for
the methyl (7, IC50 = 4.6 μM) and the trifluoromethyl (8,
IC50 = 4.0 μM) ketons as well as for the amide 9, while the
less voluminous aldehyde (6, IC50 = 0.9 μM) was slightly
more potent. The trend that straight electron-withdrawing
substitution in position 3 of the indole increases biochemical
a Biochemical assays for the SAR determination were performed
using Caliper LifeSciences electrophoretic mobility shift technology. IGF-
1R (0.1 ng/μL, BPS BioScience, CA) or InsR (0.02 ng/μL, Carna Bios-
ciences, Kobe, Japan) was incubated with a dose titration of inhibitor
(final 1% DMSO), 1 μM substrate peptide (FITC-KKSRGDYMTMQIG-
NH2), and ATP at the respective Kms of 15 and 50 μM ATP, for 90 min at
25 °C. b Mean ( standard deviation; n = 2,c 3,d and 4.e
less active than the most potent 3-cyano-5-fluoro-indol-7-yl
molecule (11).
Nevertheless, the successful biochemical optimization of
screening hit 1 prompted us to analyze the series in more
detail. Compounds from Table 1 were tested in the capture
ELISA assay to assess their inhibitory activity on IGF-1-
induced IGF-1R phosphorylation in MCF-7 breast cancer
cells. These IGF-1R inhibitors had moderate cellular activity
with IC50 values ranging from 2.2 up to 40 μM.
The IGF-1R inhibitors 1-12 were also tested in recombi-
nant enzyme and cellular phospho-insulin receptor kinase
(InsR) assays to assess their activity in this context. In the
recombinant enzyme assay, all of the compounds (except
one) show a higher activity on IGF-1R by factors ranging
from 1.4 (7) to 23 (10). The exception is the unsubstituted
4-indolyl derivative 3 (which shows a higher activity on the
activity was confirmed with the 3-cyano derivatives 10 (IC50
=
0.4 μM) and 11 (IC50 = 0.2 μM). Both compounds showed a
submicromolar IC50 and were up to 50-fold more potent than
starting point 1. In addition to the electronic properties, also
steric aspects of indolyl substituents had an influence on
IGF-1R inhibition. This was demonstrated with the 3-cyano
indol-4-yl isomer 12 (IC50 = 3.5 μM), which is by a factor of 18
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Figure 2. X-ray structure of 10 in IGF-1R and schematic description of the interactions of 10 with the allosteric IGF-1R binding site.
Scheme 1. Synthesis of Compounds 1-12a
a Conditions: (a) (i) DCM, AlCl3, 4-chlorobutyric acid chloride; (ii) THF, sodium bis(2-methoxyethoxy)aluminum hydride. (b) (i) 4-(tert-Butoxycar-
bonyl amino) piperidine, DIPEA, AcCN; (ii) 1 N HCl, dioxane. (c) THF, NMM, HOBt, EDCI, corresponding indole acid.25
InsR by a factor of 6). The cellular assays highlight the
IGF-1R selectivity of the compounds. In comparison to the
activities against the IGF-1R, all of the inhibitors demon-
strated cellular InsR IC50 values greater than 30 μM.26 The
most potent derivatives 10 and 11 showed a difference in
activity against the IGF-1R and InsR by factors of 6 and 14,
respectively.
In addition, the 5-nitrile group is found in the H-bond
distance to a water molecule located in the interface of the
side chains of Lys 1033 and Glu 1050 and the backbone
carbonyl of Phe 1047. These results are in clear agreement
with the activity of further screening hits regarding the
importance of the indole NH donor functionality and the
role of the nitrile.30 The n-butyl chain forms van der Waals
interactions to the side chains of Met 1054, His 1133, Ile
1151, and Phe 1131 on one side. On the opposite site, the
n-butyl chain is in contact with a vast cluster of water
molecules. Two water molecules of this cluster mediate
H-bonds between the piperidine N-atom and the side chain
of Asp 1153. Apart from van der Waals interactions to His
1133, the piperidine ring is mainly surrounded by the afore-
mentioned cluster of water molecules. As previously men-
tioned, the attached second 3-cyano indole ring is not defined
in the electron density map, reflected by a position already
exposed to the protein surface. However, several polar (Arg
1134 and Asp 1135) and lipophilic amino acids (Leu 1174, Pro
1175, Phe 1189, and Tyr 1165) are in the vicinity of this distal
indole ring, indicating a degree of influence of this region on
inhibitor binding as seen in the SAR.
A superimposition of the crystal structures of IGF-1R in
complex with 10 and the apo structure of the unphosphorylated
form (PDB code 1P40) revealed significant conformational
changes in the activation loop, especially regarding Phe 1154
from the DFG motif (“Phe-out”), but only moderate changes in
the relative positions of the GC loop and RC helix (Figure 3A).
This “Phe-out” conformation is similar to the corresponding
Phe 1151 in the apo structure of the unphosphorylated InsR
(Figure 3B). However, the GC loop and RC helix are significantly
repositioned as observed before for the IGF-1R-0P and InsR-0P
To further characterize the binding mode of these com-
pounds, 10 was cocrystallized with the kinase domain of
human IGF-1R. The crystal structure was solved at 1.8 Å and
shows the typical bilobal kinase fold with the helical C-terminal
lobe and the N-terminal lobe comprised of 5-stranded
β-sheets and the RC helix. On the basis of published data,
a nonphosphorylated IGF-1R construct containing two mu-
tations (E1097A and E1099A) was used.27 There are four
molecules in the asymmetric unit with slightly different
overall conformations. Minor differences exist mainly re-
garding the opening of N- and C-terminal lobes, which
correlates with the conformation of the flexible activation
loop. Because of this flexibility, some parts of the activation
loop are disordered. The binding position of the ligand is
clearly defined in the electron density map except for the
3-cyano indolyl carboxamide substituent, which has been
included in a most reasonable conformation in the final
model, but with occupancy set to 0. In contrast to other
published IGF-1R inhibitors,28,29 10 did not bind in the ATP
binding site but to an adjacent binding pocket next to the
DFG motif and the activation loop (type III binding). The
5-cyano indole ring is sandwiched between the side chains of
Met 1054 and Met 1079 and recognized via an H-bond
between the indole NH and the main chain carbonyl oxygen
atom of Val 1063 (Figure 2).
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Figure 3. (A)Comparison of the X-ray structures of 10 in IGF-1R (magenta) with the apo structure of unphosphorylated IGF-1R (dark gray)
showed an induced fit of the activation loop including Phe 1154 but only slight changes regarding the GC loop and RC helix. (B)The position
of Phe 1154 in the X-ray structures of 10 in IGF-1R (magenta) corresponds to that in InsR (green), but significant conformational differences
are observed regarding the GC loop and RC helix. The binding site for the indole ring of 10 is blocked by Met 1051 and Met 1076.
apo structures.21 The amino acids directly interacting with 10 in
IGF-1R are conserved in InsR, but the binding site of the indole
ring of 10 is partially blocked by Met 1051 and Met 1076. These
conformational differences result in altered shapes of the
allosteric pockets, which might explain the observed selectivity
of 1-12 against InsR on a cellular screening level. These
detailed insights into the binding mode of 10 to IGF-1R are
helpful to explain the results of our synthetic work and give hints
about the mode of action of these allosteric IGF-1R inhibitors.
In conclusion, the structural analysis of hit 10
(MSC1609119A-1) has revealed an allosteric binding mode,
and contributing amino acid contacts were identified. The
mostpotent biochemical IGF-1R compound11 isbya factorof
50 more potent than the original screening hit 1. The com-
pounds have cellular activity in the phospho-IGF-1R ELISA
assay and, as indicated, do not influence IR signaling signifi-
cantly up to concentrations of 30 μM. These hits and their
binding mode to IGF-1R could serve as a starting point to
generate even more pronounced selectivity against InsR.
ACKNOWLEDGMENT We thank Proteros, Munich, for the pre-
paration of the IGF-1R X-ray cocrystal structure, Uwe Eckert and
Nicole Lange for the preparation of the compounds, Irina Bersch for
the performance of the cellular assays, and Ben Askew for valuable
discussions.
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