.
Angewandte
Communications
DOI: 10.1002/anie.201403936
Drug Design Hot Paper
Tumor-Targeting of EGFR Inhibitors by Hypoxia-Mediated
Activation**
Claudia Karnthaler-Benbakka, Diana Groza, Kushtrim Kryeziu, Verena Pichler,
Alexander Roller, Walter Berger, Petra Heffeter,* and Christian R. Kowol*
[3]
Abstract: The development of receptor tyrosine-kinase inhib-
itors (TKIs) was a major step forward in cancer treatment.
However, the therapy with TKIs is limited by strong side effects
and drug resistance. The aim of this study was the design of
novel epidermal growth factor receptor (EGFR) inhibitors that
azolines as the most potent representatives. Among them,
the EGFR inhibitors gefitinib (Iressa) and erlotinib (Tarceva;
Figure 1) were the first to be approved in 2003 and 2004,
respectively, for the treatment of locally advanced or meta-
III
are specifically activated in malignant tissue. Thus, a Co -
based prodrug strategy for the targeted release of an EGFR
inhibitor triggered by hypoxia in the solid tumor was used.
New inhibitors with chelating moieties were prepared and
tested for their EGFR-inhibitory potential. The most promising
III
candidate was coupled to Co and the biological activity tested
in cell culture. Indeed, hypoxic activation and subsequent
EGFR inhibition was proven. Finally, the compound was
tested in vivo, also revealing potent anticancer activity.
T
yrosine kinases play a key role in human signal transduction
processes, leading to cell growth and differentiation. Recent
advances have implicated their role in the pathophysiology of
[
1]
Figure 1. Chemical structures of gefitinib (Iressa; top) and erlotinib
cancer. For example, overexpression of the epidermal
growth factor receptor (EGFR, erbB1), a receptor tyrosine
kinase, has been observed in a wide range of solid tumors,
including those of head and neck, lung, colon, ovary, and
(Tarceva; bottom).
static non-small-cell lung carcinoma (NSCLC) with activating
[2]
[2]
breast, and has frequently been linked to a poor prognosis.
EGFR mutations. Additionally, erlotinib has been approved
Thus, inhibition of the EGFR has emerged as an attractive
strategy in anticancer drug research. A large number of small-
molecule inhibitors has been developed, with 4-anilinoquin-
as first-line treatment of metastatic pancreatic cancer in
[
4]
combination with gemcitabine. However, despite the bene-
fits of EGFR tyrosine-kinase inhibitors (TKIs) and their
increasing clinical use, drug-resistance development, insuffi-
cient tumor accumulation, and the occurrence of severe side
effects, such as papulopustular skin rash, are major limitations
[
+]
[
*] M. Sc. C. Karnthaler-Benbakka, Dr. V. Pichler, Dipl.-Ing. A. Roller,
[
5]
Dr. C. R. Kowol
for successful treatment.
Institute of Inorganic Chemistry, University of Vienna
Waehringer Strasse 42, 1090 Vienna (Austria)
E-mail: christian.kowol@univie.ac.at
One promising approach to reduce the adverse effects of
anticancer agents is to increase tumor selectivity by the use of
prodrug systems. This concept is based on nontoxic com-
pounds which release the corresponding active drugs only
[
+]
M. Sc. D. Groza, Mag. K. Kryeziu, Prof. Dr. W. Berger,
Dr. P. Heffeter
[
6]
after specific activation in cancerous tissues. For prodrug
activation several cancer-targeting mechanisms have been
reported, one of which being activation by reduction in the
Institute of Cancer Research, Medical University of Vienna
Borschkegasse 8A, 1090 Vienna (Austria)
E-mail: petra.heffeter@meduniwien.ac.at
[7]
Prof. Dr. W. Berger, Dr. P. Heffeter, Dr. C. R. Kowol
Research Platform “Translational Cancer Therapy Research”
University of Vienna and Medical University of Vienna
Vienna (Austria)
inherently hypoxic tissue found in most solid tumors. This
concept is of additional interest, since especially tumor cells
that grow under anaerobic conditions develop resistance to
[8]
chemotherapeutic agents.
+
[
] These authors contributed equally to this work.
Cobalt(III) compounds can be used as such bioreducible
[
**] This work was supported by the Fonds der Stadt Wien fꢀr innovative
interdisziplinaere Krebsforschung, the FWF (P26603), and the COST
action CM1105. We thank Prof. Mag. Dr. Walter Weissensteiner,
University of Vienna, for helpful discussions. The authors declare
a conflict of interest, as the lead compound is covered by a patent
application.
III
II
prodrugs due to the Co /Co redox potential, which can be
[8,9]
tuned to the range of cellular reductants,
cant difference in the ligand lability of the two oxidation
and the signifi-
[
10]
6
III
states. While octahedral d low-spin Co complexes are
7
kinetically inert, labile d high-spin complexes are formed
after reduction. In the absence of oxygen, which would
immediately lead to re-oxidation, Co complexes easily
[
9a]
II
1
2930
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 12930 –12935