| Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
OPEN ACCESS PLUS
Contents
Cilengitide: The First
Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis
and Clinical Evaluation,
2010, 10, 753-768
Carlos Mas-Moruno, Florian Rechenmacher and Horst
Kessler
[Abstract]
[Full
Text Article]
Pharmacogenomics of Human ABC Transporter ABCC11 (MRP8): Potential
Risk of Breast Cancer and Chemotherapy Failure,
2010, 10, 617-624
Yu Toyoda and Toshihisa Ishikawa
[Abstract] [Full
Text Article]
Targeting RSK: An Overview of Small Molecule Inhibitors,
2008, 8, 710-716
T.L. Nguyen
[Abstract] [Full
Text Article]
Regulation of the Endoplasmic Reticulum Ca2+-Store
in Cancer, 2008, 8, 705-709
A. Bergner and R.M. Huber
[Abstract] [Full
Text Article]
The Protein Kinase Inhibitor Balanol: Structure–Activity
Relationships and Structure-Based Computational Studies,
2008, 8, 638-645
V. Pande, M.J. Ramos and F. Gago
[Abstract] [Full
Text Article]
Role of Mismatch Repair and MGMT in Response to Anticancer
Therapies, 2008, 8, 368-380
I. Casorelli, M.T. Russo and M.
Bignami
[Abstract] [Full
Text Article]
Inhibition of Protein Kinase c-Src as a Therapeutic Approach
for Cancer and Bone Metastases, 2008,
8, 342-349
N. Rucci, M. Šuša and A. Teti
[Abstract] [Full
Text Article]
Programmable DNA Binding Oligomers for Control of Transcription,
2005, 5, 373-387
Peter B. Dervan, Raymond M. Doss and
Michael A. Marques
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Cilengitide: The First Anti-Angiogenic Small Molecule
Drug Candidate. Design, Synthesis and Clinical Evaluation
Carlos Mas-Moruno, Florian Rechenmacher and Horst
Kessler
[Full
Text Article]
Cilengitide, a cyclic RGD pentapeptide, is currently in clinical
phase III for treatment of glioblastomas and in phase II for
several other tumors. This drug is the first anti-angiogenic
small molecule targeting the integrins αvβ3,
αvβ5
and α5β1.
It was developed by us in the early 90s by a novel procedure,
the spatial screening. This strategy resulted in c(RGDfV),
the first superactive αvβ3
inhibitor (100 to 1000 times increased activity over the linear
reference peptides), which in addition exhibited high selectivity
against the platelet receptor αIIbβ3.
This cyclic peptide was later modified by N-methylation
of one peptide bond to yield an even greater antagonistic
activity in c(RGDf(NMe)V). This peptide
was then dubbed Cilengitide and is currently developed as
drug by the company Merck-Serono (Germany).
This article describes the chemical development of Cilengitide,
the biochemical background of its activity and a short review
about the present clinical trials. The positive anti-angiogenic
effects in cancer treatment can be further increased by combination
with “classical” anti-cancer therapies. Several
clinical trials in this direction are under investigation.
[Back to top]
Pharmacogenomics of Human ABC Transporter ABCC11 (MRP8):
Potential Risk of Breast Cancer and Chemotherapy Failure
Yu Toyoda and Toshihisa Ishikawa
[Full
Text Article]
Some genetic polymorphisms of human ABC transporter genes
are reportedly related to the risk of certain diseases and
patients’ responses to medication. Human ABCC11 functions
as an ATP-dependent efflux pump for amphipathic anions. One
nonsynonymous SNP 538G>A (Gly180Arg) has been found to
greatly affect the function and stability of de novo
synthesized ABCC11 (Arg180) variant protein. The SNP variant
lacking N-linked glycosylation is recognized as a
misfolded protein in the endoplasmic reticulum (ER) and readily
undergoes proteasomal degradation. This ER-associated degradation
of ABCC11 protein underlies the molecular mechanism of affecting
the function of apocrine glands. On the other hand, the wild
type (Gly180) of ABCC11 is associated with wet-type earwax,
axillary osmidrosis, colostrum secretion from the mammary
gland, and the potential susceptibility of breast cancer.
Furthermore, the wild type of ABCC11 reportedly has ability
to efflux cyclic nucleotides and nucleoside-based anticancer
drugs. The SNP (538G>A) of the ABCC11 gene is
suggested to be a clinical biomarker for prediction of chemotherapeutic
efficacy. Major obstacle to the successful chemotherapy of
human cancer is development of resistance, and nucleoside-based
chemotherapy is often characterized by inter- individual variability.
This review provides an overview about the discovery and the
genetic polymorphisms in human ABCC11. Furthermore,
we focus on the impact of ABCC11 538G>A on the
apocrine phenotype, patients’ response to nucleoside-based
chemotherapy, and the potential risk of breast cancer.
[Back to top]
Targeting RSK: An Overview of Small
Molecule Inhibitors
T.L. Nguyen
[Full Text Article]
Ribosomal S6 kinase (RSK) is a family of serine/threonine
kinases that has been identified as a promising anti-cancer
target. While a number of protein kinase inhibitors that have
potent activity against other serine/threonine kinases were
shown to also inactivate RSK, there is keen interest in the
three different inhibitor chemotypes that were shown to be
RSK specific, since these compounds have tremendous utility
as chemical probes in elucidating the biochemistry of the
RSK signaling cascade and unraveling the molecular basis of
cancer. Because each compound may have therapeutic potential,
the nonspecific kinase inhibitors as well as the RSK specific
inhibitors will be discussed.
[Back to top]
Regulation of the Endoplasmic Reticulum Ca2+-Store
in Cancer
A. Bergner and R.M. Huber
[Full Text Article]
Calcium is a ubiquitous second messenger and is
involved in virtually all cellular functions. Cellular events
being regulated by calcium include gene transcription, metabolism,
proliferation and apoptosis. Cancer growth is based on increased
proliferation, decreased differentiation and decreased apoptosis.
Therefore, the intracellular Ca2+-homeostasis
has become one of the focuses in current cancer research.
Elevation of the cytoplasmic Ca2+-concentration
can result from Ca2+-influx
from the extracellular space or from Ca2+-release
from intracellular stores. The main intracellular Ca2+-store
is the endoplasmic reticulum (ER). The Ca2+-content
of the ER is maintained by trans-membrane proteins involving
the sarco/endoplasmic reticulum Ca2+-ATPase
and the inositol-1,4,5-phosphat receptor. In this review,
we summarize the current knowledge of the ER and its trans-membrane
proteins as regulating structures of the intracellular Ca2+-homeostasis,
what changes occur in malignant cells and how this promotes
cancer. We further review possible pharmacological intervention
and show future perspectives of the intracellular Ca2+-homeostasis
as an anti-cancer target.
[Back to top]
The Protein Kinase Inhibitor Balanol: Structure–Activity
Relationships and Structure-Based Computational Studies
V. Pande, M.J. Ramos and F. Gago
[Full
Text Article]
Balanol, a fungal metabolite, is a potent ATP-competitive
inhibitor of Protein Kinase C (PKC) and Protein Kinase A (PKA),
important targets in oncology. Since its discovery in 1993,
a number of studies have been performed in order to design
selective and bioavailable balanol analogs. Several crystal
structures of PKA in complex with balanol and a few analogs
bound within the catalytic site have also been solved providing
insight about the key interactions for binding. The PKA-balanol
complex has also served as an interesting model system for
structure-based ligand design and validation of a number of
computational methodologies aimed at both understanding the
physical basis for molecular recognition and addressing the
important issue of protein flexibility in ligand binding.
We provide an overview of the structure-activity relationships
of balanol analogs and summarize the progress made in structural
and computational studies involving balanol.
[Back to top]
Role of Mismatch Repair and MGMT in Response to Anticancer
Therapies
I. Casorelli, M.T. Russo and M. Bignami
[Full
Text Article]
Tumor resistance to cytotoxic chemotherapy drugs and
their toxicity to normal cells are major clinical obstacles
to anticancer therapy effectiveness. Alterations in various
DNA repair pathways play a key role in the development of
both mechanisms of drug resistance and toxicity. Since deregulation
of the DNA damage response and alterations in DNA repair pathways
are relatively common in human cancer, the knowledge of these
alterations in cancer cells would be an important predictive
factor for the clinical response to chemotherapy and a useful
guide in designing an appropriate therapeutic strategy.
This review is focused on the mismatch repair (MMR) pathway
and the O6 -methylguanine-DNA-methyltransferase
(MGMT) repair protein. In particular, we examine how inactivation
of these DNA repair mechanisms might affect the response of
tumor cells to chemotherapy, with a special emphasis on agents
inducing methylation and oxidative DNA damage and interstrand
DNA cross-links (ICLs). In addition, we provide novel experimental
evidence indicating that MMR is required for efficient repair
of ICLs via stabilization of RAD51 containing repair
intermediates. Finally, we discuss possible emerging therapeutical
strategies for treating MMR-defective tumors.
[Back to top]
Inhibition of Protein Kinase c-Src as a Therapeutic
Approach for Cancer and Bone Metastases
N. Rucci, M. Šuša and A. Teti
[Full
Text Article]
c-Src is a proto-oncogene involved in the genesis of
and invasion by many cancers. This non-receptor tyrosine kinase
also plays a crucial role in bone homeostasis, since inhibition
or deletion of c-Src impairs the function of osteoclasts,
the bone resorbing cells. It is thus conceivable that c-Src
could be a suitable target for the pharmacological treatment
of cancers, skeletal metastases and diseases of bone loss,
such as osteoporosis. The pyrrolo-pyrimidines CGP77675 and
CGP76030 proved to be effective in preventing bone loss in
animal models, while the effect of AZD0530, a dually active
inhibitor of c-Src and Bcr-ABL, on bone resorption, has been
tested in a Phase I clinical trials with promising results.
As far as the metastatic bone disease is concerned, c-Src
inhibitors could potentially have inhibitory effects both
on osteoclasts and on tumour cells, and could disrupt the
vicious circle established between these cell types in the
bone microenvironment. In accord with this idea, CGP76030
is able to reduce the incidence of osteolytic lesions and
of visceral metastases, and to suppress morbidity and lethality
in a bone metastasis mouse model without obvious adverse effects.
The purine-based c-Src inhibitor AP23451 and the dual c-Src/Abl
inhibitors AP22408 and AP23236 proved efficacious in reducing
bone metastases in preclinical studies. These results open
a new avenue for the development of innovative therapies for
the treatment of bone metastatic disease.
[Back to top]
Programmable DNA Binding Oligomers for Control of Transcription
Peter B. Dervan, Raymond M. Doss and Michael A. Marques
[Full
Text Article]
Mapping and sequencing the genetic blueprint in human, mice,
yeast and other model organisms has created challenges and
opportunities for chemistry, biology and human medicine. An
understanding of the function of each of the ~ 25, 000 genes
in humans, and the biological circuitry that controls these
genes will be driven in part by new technologies from the
world of chemistry. Many cellular events that lead to cancer
and the progression of human disease represent aberrant gene
expression. Small molecules that can be programmed to mimic
transcription factors and bind a large repertoire of DNA sequences
in the human genome would be useful tools in biology and potentially
in human medicine. Polyamides are synthetic oligomers programmed
to read the DNA double helix. They are cell permeable, bind
chromatin and have been shown to downregulate endogenous genes
in cell culture.
|
