Natural product derived receptor tyrosine kinase inhibitors: Identification of IGF1R, Tie-2, and VEGFR-3 inhibitors

Article abstract of DOI:10.1002/1521-3773(20020402)41:7<1174::AID-ANIE1174>3.0.CO;2-V

Blood and lymph vessel growth is regulated by Tie-2 and the VEGFR-3 receptor tyrosine kinases. These proteins also play major roles in the growth and metastasis of cancers. A novel class of inhibitors of these signal-transducing proteins, and of the IGF1R

Full text of DOI:10.1002/1521-3773(20020402)41:7<1174::AID-ANIE1174>3.0.CO;2-V

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principle for the development of relatively small compound
libraries, which should yield significantly higher hit-rates than
much larger libraries, designed exclusively on the basis of
available and proven chemical transformations.
In the light of this concept, we synthesized a library of 56
nakijiquinone analogues (Scheme 1), the only natural prod-
ucts known to be inhibitors of the Her-2/Neu receptor
tyrosine kinase,[15] and investigated these analogues as possi-
ble inhibitors of the receptor tyrosine kinases involved in
angiogenesis.
Natural Product Derived Receptor Tyrosine
Kinase Inhibitors: Identification of IGF1R,
Tie-2,and VEGFR-3 Inhibitors**
Petra Stahl, Lars Kissau, Ralph Mazitschek,
Athanassios Giannis,* and Herbert Waldmann*
Angiogenesis, the development of new blood vessels from
pre-existing ones, is central to wound repair, inflammation,
and embryonic development. Furthermore, aberrant angio-
genesis is considered to be a key step in tumor growth, spread,
and metastasis.[1, 2] Vascular development depends on endo-
thelium-specific receptor tyrosine kinases, in particular the
H-bond donor
H-bond
vascular endothelial growth factor receptors
1 3
donor
R
(VEGFR1 3) and the Tie-2 receptor.[3] All these receptors
OH
8]
have been implicated in tumor angiogenesis,[4 and antago-
HN
H-bond
acceptor
O
O
O
hydrophilic
part
nization of Tie-2, VEGFR-2, or VEGF-D (a ligand of
VEGFR-3) inhibits tumor growth and tumor metastasis
in vivo.[7, 9, 10] The development of low molecular weight
inhibitors of these receptor tyrosine kinases is among the
most promising approaches to the development of new,
alternative antitumor drugs, and several inhibitors of
VEGFR-2 are in clinical trials.[11, 12] The combination of
VEGFR-2 inhibitors with Tie-2 antagonists should potentiate
their anti-angiogenic effects.[6] Furthermore, inhibitors of
VEGFR-3 would suppress the metastasis of lymphogenic
tumors. To date however, only a few cases of small-molecule
inhibitors of the Tie-2 and VEGFR-3 receptors have been
reported.[13] Herein we describe the identification of inhibitors
of these proteins from a compound library that was derived
from a natural product.
H-bond
acceptor
OH
H
hydrophobic
part
H-bond donor
L-serine L-threonine D-threonine D-valine glycine
R
HN COOH
O
O
O
O
O
O
O
O
We have recently proposed a new concept for enhancing
the process of finding lead compounds, by use of combina-
torial methods.[14] The key principle of this concept is to
employ natural products with known biological activity as
biologically validated starting points in structural space, which
are selected by evolution for binding to structurally con-
served, yet genetically mobile protein domains. The frame-
works of such natural products may then serve as a guiding
OH
AA
OH
H
Nakijiquinones
[*] Prof. Dr. H. Waldmann, Dr. P. Stahl, Dipl.-Chem. L. Kissau
Max-Planck-Institut f¸r molekulare Physiologie
Abteilung Chemische Biologie
Scheme 1. Structure of the nakijiquinones and plan for the synthesis of
nakijiquinone analogues.
Otto-Hahn-Strasse 11, 44227Dortmund (Germany)
Fax : (‡49)231-133-2499
and
Universit‰t Dortmund, Fachbereich 3
Organische Chemie, 44221 Dortmund (Germany)
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
The design of the nakijiquinones analogues was based on
the modular structure of the natural products. The nakijiqui-
nones consist of a hydrophobic diterpene unit, which may
interact with a hydrophobic pocket close to the ATP binding
site,[12] a quinone-type building block, and an amino acid, the
latter two of which may participate in hydrogen bonding to
the ATP binding site of kinases. Consequently, the diterpene
part was replaced with simple hydrophobic structures
(Scheme 1). The hydrophilic amino acids serine and threo-
nine, and the hydrophobic acids valine and glycine were
chosen, and the stereochemistry was also varied. To modify
the type and number of hydrogen-bond donors and acceptors,
we introduced either one or two amino acids, an amino acid
and an OH group, or only one amino acid.
Prof. Dr. A. Giannis, Dipl.-Chem. R. Mazitschek
Institut f¸r Organische Chemie
Universit‰t Karlsruhe
Richard-Willst‰tter-Allee 2, 76128 Karlsruhe (Germany)
Fax : (‡49)721-608-7652
E-mail: giannis@ochhades.chemie.uni-karlsruhe.de
[**] This research was supported by the Fonds der Chemische Industrie.
R.M. is grateful to the State of Baden-W¸rttemberg for a scholarship
from the Landesgraduiertenfˆrderung. L.K. is grateful to the Stud-
ienstiftung des deutschen Volkes and the Fonds der Chemische
Industrie for scholarships; IGF1R ˆ insulin-like growth factor 1
receptor, Tie-2 ˆ tyrosine kinase with immunoglobulin and epidermal
growth factor homology domains, also called Tek, VEGFR-3 ˆ vas-
cular endothelial growth factor receptor 3.
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Scheme 2 shows the majority of the library members that
were synthesized. A series of analogues was built up, in which
the diterpene unit was replaced either by a benzyl group, a
cyclohexane ring, a n-butyl group (structure not shown), or by
The same aromatic building blocks and the oxygenation/
amino acid introduction methodology were employed in the
synthesis of analogues with a decalin system. Linkage to a
trans-decalin building block with an exocyclic double bond
was achieved by the Suzuki coupling of substituted arylbor-
onic acids to the corresponding decalin-derived vinyl bromide
(a representative example is given in Scheme 4). Reduction of
the double bond in the Suzuki products yielded analogues
with an alkyl side chain attached to the decalin core.
OMe
R
NH-AA
NH-L-Ser
O
O
O
O
O
O
O
O
R
HN-AA
R
NH-L-Ser
R = OMe, AA
Br
R = H, OMe
O
R = OMe, AA
AA = L-Ser, L-Thr,
D-Thr, D-Val
a
AA = L-Ser, L-Thr,
D-Thr, D-Val, Gly
OMe
b
OMe
OMe
OMe
OMe
OMe
(HO)2B
OiPr
O
O
iPrO
OMe
R
OiPr
O
O
OMe
O
OMe
OMe
R =
NH-AA
NH-AA
O
HN
COOH
O
AA = L-Ser, L-Thr,
D-Thr, D-Val, Gly
OiPr
O
c–f
O
O
HN-AA
OH
OH
Scheme 4. Synthesis of
a decalin analogue of the nakijiquinones.
R
NH-AA
NH-AA
a) BrCH2PPh3Br, KOtBu, THF, À788C !RT, 63%; b) [Pd(PPh3)4], tol-
uene, EtOH, Na2CO3, 908C, 24 h, 74%; c) BCl3, CH2Cl2, 08C, 89%;
d) ON(SO3K)2, H2O, benzene, aliquat 336, Na2CO3, 78%; e) KOH,
MeOH, H2O, 59%; f) d-valine, NaHCO3, EtOH, 56%.
O
O
AA = L-Ser,
D-Thr, D-Val, Gly
R =
O
O
HN-AA
OH
Scheme 2. Representative members of the nakijiquinone library.
These syntheses gave access to a compound library with
56 members, which was screened for possible inhibitors
against receptor tyrosine kinases, selected to cover a wide
spectrum of biological activities.
a hydrogen atom. In general, these compounds were synthe-
sized from appropriately substituted and selectively protected
phenolic ethers, by means of a reaction sequence consisting of
selective deprotection, oxidation to the quinoid system, and
addition of an amino acid to the resulting vinylogous esters
(by analogy to the methods described in the total synthesis of
the nakijiquinones; a representative example is given in
Scheme 3).[15]
To this end, in addition to VEGFR-2 (KDR, flk-1),
VEGFR-3 (flt-4), and Tie-2, Her-2/Neu, epidermal growth
factor receptor (EGFR; ErbB-1), ErbB-2, and insulin-like
growth factor 1 receptor (IGF1R) were also chosen. The Her-
2/Neu proto-oncogene belongs to the EGF family of receptor
tyrosine kinases. It is over-expressed in approximately 30% of
all primary breast, ovary, and stomach cancers.[16] The EGFR,
which is closely related to Her-2/Neu, has been implicated in
human tumorigenesis, for example, of glioblastoma as well as
in numerous tumors of epithelial origin including breast and
oesophageal tumors.[17] The insulin-like growth factor 1 re-
ceptor affects cell mitogenesis, survival, transformation, and
insulin-like activities by the binding of its ligands, IGF1 and
IGF2. This receptor influences post natal growth physiology,
and its activity has been associated with malignant disorders
such as breast cancer.[18] The anti-apoptotic effect induced by
the IGF1/IGF1R system correlates to the induction of
chemoresistance in various tumors.[19]
OMe
HN
HN
COOH
HO
OMe
O
iPrO
a, b
c, d
O
Br
COOH
Scheme 3. Synthesis of an amino acid substituted quinone. a) nBuLi, THF,
À788C, 30 min, then CuI !408C; À788C, benzyl bromide, THF, 55%;
b) BCl3, CH2Cl2, 08C, 88%; c) O2, N,N×-ethylenebis(salicylideneiminato)-
cobalt(ii)(salcomine), DMF, 70%; d) d-valine, NaHCO3, EtOH, 75%.
Angew. Chem. Int. Ed. 2002, 41, No. 7
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1175

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Out of the 56 compounds subjected to the kinase assay, five
compounds displayed inhibitory activity in the low micro-
molar range. The library of the nakijiquinone analogues did
not contain any inhibitor of Her-2/Neu, EGFR, ErbB-2, or
VEGFR-2 which warranted further investigation. Remark-
ably, four of the compounds investigated turned out to be
inhibitors of the Tie-2 receptor (Table 1). Two of these
(entries 1 and 2) proved to be selective for this kinase; the
other kinases in the assay were not significantly inhibited at
concentrations of up to 70 mm. In the light of these findings, 14
close analogues of the nakijiquinones, as well as synthetic
nakijiquinones A, C, and D,[15] were investigated as inhibitors
of the kinases described above; however, no further inhibitor
was found.
The most potent inhibitor identified in this study is
bisthreonine derivative 3 (entry 3), which not only inhibits
the Tie-2 receptor with an IC50 value of 5 mm, but also
demonstrates a similar activity against VEGFR-3. These
results indicate that 3 may be of interest in the inhibition of
angiogenesis in general, and in the prevention of lymphangio-
genesis in particular. Furthermore, the functionalization of
the central six-membered ring with two amino acid residues
suggests that improvements in activity and selectivity may be
possible by variation of the amino acid residues.
The data given in Table 1 indicate that a quinoid system
flanked by a hydrophobic group (entries 1 and 2) may be
important for binding. Thus, the corresponding quinoid
compound, analogous to 1 and 2 but lacking a further
hydrophobic substituent, inhibits neither Tie-2 nor VEGFR-
3. The presence of an amino acid as a vinylogous amide seems
to enhance inhibitory activity, probably by providing a
hydrogen-bond donor/hydrogen-bond acceptor motif. Nota-
bly, compound 4 inhibits the IGF1 receptor selectively with an
IC50 value of 500 nm. The finding that this small nakijiqui-
none-analogue library yielded two IGF1R inhibtors indicates
that this class of compounds in general may provide a suitable
lead structure for the development of more potent IGF1R
inhibitors.
Detailed analysis of the inhibitory activity of 3 revealed that
it is a competitive inhibitor and competes with ATP for the
binding site of the nucleotide triphosphate. The Ki value and
KM values were found to be 3 mm and 19 mm, respectively
(with ATP as the substrate).
To rationalize the selectivity displayed, for example, by
compound 4, which embodies a quinoid system and a hydro-
phobic annelated ring system and thereby closely resembles
the nakijiquinones, the potential binding modes to Tie-2 were
investigated by means of molecular modeling experiments. To
this end, homology models were constructed for VEGFR-2,
VEGFR-3, and Tie-2, which used the available crystal
structures of FGFR-1 as templates (Figure 1).[12, 14, 20] Al-
though an X-ray crystal structure of Tie-2 (apo-enzyme) has
been reported,[21] it does not provide a suitable basis for
modeling experiments as receptor tyrosine kinases are known
to undergo significant conformational changes upon ligand
binding.
The homology models of the Tie-2, VEGFR-2, and
VEGFR-3 kinase domains were constructed by using
CHARMM,[22] MODELLER,[23] WHATCHECK,[24] and Wit-
notP,[25] and employed the available crystal structures of the
FGF receptor 1 as templates. The crystal structures of the
FGF receptor 1 were chosen because of their good sequence
agreement within the kinase domain with VEGFR-3
(ꢀ51%), Tie-2 (ꢀ45%), and VEGFR-2 (ꢀ56%). These
values are above the 30% minimum, usually considered to be
the limit for a good homology model.[26] The primary align-
ment was performed by DIALIGN[27] and corrected manually.
For the purpose of building the homology models, the residues
of the kinase insert domain were deleted from the sequences.
The choice of orientation of the inhibitors within the ATP
binding sites was guided by our previous work[15] and by the
interactions described by Mohammadi et al.[20] After manual
Table 1. Inhibition of different receptor tyrosine kinases by nakijiquinone analogues.
IC50 for receptor [mm][a]
Entry
1
Compound
EGFR
Her-2/Neu
ErbB-2
IGF1R
VEGFR-2
VEGFR-3
Tie-2
18
2
14
5
3
6
3
4[b]
0.5
9
[a] To assay the inhibitory activity, the kinase-catalyzed phosphorylation of poly(Glu-Tyr) in the presence of varying concentrations of inhibitor was
determined. The kinases were employed as fusion proteins of glutathione-S-transferase (GST) and the respective kinase domain. The relative amount of
phosphorylated substrate was quantified by means of an anti-phosphotyrosine enzyme-linked immunosorbent assay (ELISA), which employed an anti-
phosphotyrosine antibody conjugated to horseradish peroxidase (POD). The bound antibody was detected by the light emission after addition of a
chemiluminescence substrate for POD. [b] Compound 4 was investigated as an inseparable mixture of diastereomers.
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Figure 1. Alignment of amino acid sequences of VEGFR-2, VEGFR-3, Tie-2, and FGFR-1. The sequences were obtained from the Swiss Prot database
(VEGFR-2: P35968, VEGFR-3: P35916, Tie-2: Q02763, FGFR-1: P11362).
docking, the energy of the ligand protein complex was
minimized by using CHARMM.[22] According to these inves-
tigations, 4 binds in the mode shown in Figure 2. Compound 4
inhibits Tie-2 in the low micromolar range, but demonstrates
We have shown that a relatively small library based on a
naturally occurring kinase inhibitor yields potent inhibitors
for other kinases with a high hit rate. This led to the
identification of IGF1R, Tie-2, and VEGFR-3 inhibitors.
These results may open up entirely new opportunities for the
suppression of angiogenesis and lymphangiogenesis, and for
the development of new anti-cancer drugs. Moreover, the
results support our proposed concept for the enhancement of
the hit and lead finding process.[14] The results show that to
achieve high hit rates, the synthesis of natural product derived
libraries is necessary to counterbalance the varying amino
acid sequences found in repeatedly occurring protein domains
with similar structures (here the kinase domains). The syn-
thesis of the natural products alone would not have yielded
the desired inhibitors.
Received: October 10, 2001 [Z18042]
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Figure 2. Proposed binding mode of compound 4 to the active site of Tie-2.
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no activity towards VEGFR-2 or VEGFR-3. We attribute this
selectivity to unfavorable interactions of the decalin moiety
with C989 in VEGFR-2 (corresponds to C900 in VEGFR-3
and A981 in Tie-2) and to the formation of a hydrogen bond
between the carboxy group of 4 and the amino acid N834 of
Tie-2 (A844 in VEGFR-2 and A855 in VEGFR-3). Com-
pound 4 binds in a manner in which the essential hydrogen
bonds to the amino acids E917, C919, and N909 may be
formed. Furthermore, amino acids I902 and I886 in Tie-2
cause the hydrophobic pocket in our model to be somewhat
smaller than the pockets in VEGFR-2 and VEGFR-3. The
decalin moiety of 4 covers the accessible surface in the
hydrophobic pocket of Tie-2 much better than in VEGFR-2,
where some space is left unoccupied.
Angew. Chem. Int. Ed. 2002, 41, No. 7
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Since the first successful experiments aimed at the direct
synthesis of organosilanes and organogermanes, carried out
by Rochow and M¸ller in 1942 1947,[1, 2] a whole industry for
the production and application of alkylchlorosilanes has
evolved. The direct synthesis of alkylgermanes, however, has
received much less attention, although alkylated polygermy-
lenes[3] and mixed polygermasilylenes,[4] the synthesis of which
requires diorganogermanium compounds, have gained in-
creasing importance as photoconducting polymers and photo-
resists. Their surface properties and their absorption maxima
depend not only on the type of polymer backbone but also on
the nature of the organic substituent on the diorganogerma-
nium compound.[3, 4]
Like the direct synthesis of alkylchlorosilanes, the oxidative
addition of alkyl halides to germanium is also clearly
exothermic [Eqs. (1) (3)].[5]
Cu
2CH3Cl ‡ Si
2C2H5Cl ‡ Si
(CH3)2SiCl2
(C2H5)2SiCl2
DHR ˆ À304 kJmolÀ1
À!
300 o
C
(1)
Cu
À!
350 o
C
Cu
2CH3Cl ‡ Ge
2CH3Br‡ Si
(CH3)2GeCl2
(CH3)2SiBr2
DHR ˆ À97kJmol À1 (2)
DHR ˆ À246 kJmolÀ1 (3)
À!
320 o
C
Cu
À!
325 o
C
Nonetheless, the direct reaction of alkyl halides with
elemental silicon or germanium requires very drastic con-
ditions (for the synthesis of an organoelement compound) and
the use of a copper catalyst [Eqs. (1) (3)]. This is due to the
pronounced kinetic inertness of the elemental tetrels. The
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use of functionalized organic halides in direct syntheses,
because these compounds lack the necessary thermal stability.
In the following, the application of solvochemically activated
germanium in direct synthesis reactions is reported. When this
very reactive form of germanium is used, the oxidative
addition takes place at conditions mild enough to allow, for
the first time, a direct synthesis of organofunctionalized
germanes without the need for a copper-containing additive.
The solvochemical activation of germanium occurs through
the reduction of its dichloride with a solution of Li[Et3BH] in
THF[6] at room temperature [Eqs. (4) and (5)]. Completely
X-ray amorphous, orange-colored germanium is obtained
under these conditions.
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THF
GeCl2 ¥ dioxane ‡ 2Li[Et3BH]
Ge* ‡ 2LiCl ‡ 2Et3B ‡ H2 ‡ dioxane (4)
À!
RT
orange
THF
GeI2 ‡ 2Li[Et3BH]
Ge* ‡ 2LiI ‡ 2Et3B ‡ H2
(5)
À!
RT
orange
[*] Dr. S. Schlecht
Max-Planck-Institut f¸r Festkˆrperforschung
Heisenbergstrasse 1, 70569 Stuttgart (Germany)
Fax : (‡49)711-689-1502
E-mail: s.schlecht@fkf.mpg.de
[**] This work was supported by a Liebig-Fellowship and a grant from the
Fonds der Chemischen Industrie and the BMBF.
1178
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4107-1178 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 7