| Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 8, Number 8, December 2008
Contents
Preamble: CDC25 Phosphatases in Cancer and CDC25 Inhibitors
Guest Editor: Grégoire Pierre Prevost
Editorial Pp. 817
Cell Cycle Control by the CDC25 Phosphatases Pp.
818-824
B. Aressy and B. Ducommun
[Abstract] [Purchase
Article]
CDC25A: A Rebel Within the CDC25 Phosphatases Family?
Pp. 825-831
A. Fernandez-Vidal, A. Mazars and S.
Manenti
[Abstract] [Purchase
Article]
In Vivo Roles of CDC25 Phosphatases:
Biological Insight into the Anti-Cancer Therapeutic Targets
Pp. 832-836
H. Kiyokawa and D. Ray
[Abstract] [Purchase
Article]
Is Cdc25 a Druggable Target? Pp.
837-842
J.S. Lazo and P. Wipf
[Abstract] [Purchase
Article]
Cdc25B Phosphatase Inhibitors in Cancer Therapy: Latest
Developments, Trends and Medicinal Chemistry Perspective
Pp. 843-856
A. Lavecchia, A. Coluccia, C. Di Giovanni
and E. Novellino
[Abstract] [Purchase
Article]
CDC25 Inhibitors as Anticancer Agents Are Moving Forward
Pp. 857-862
M.-C. Brezak, P.G. Kasprzyk, M.-O. Galcera,
O. Lavergne and G. P. Prévost
[Abstract] [Purchase
Article]
Cdc25A Protein Phosphatase: A Therapeutic Target for Liver
Cancer Therapies Pp. 863-871
Z. Wang, S. Kar and B.I. Carr
[Abstract] [Purchase
Article]
General Articles
Proliferation of Breast Cancer Cells: Regulation,
Mediators, Targets for Therapy Pp. 872-885
J. Mester and G. Redeuilh
[Abstract] [Purchase
Article]
Marine Metabolites Overcoming or Circumventing Multidrug
Resistance Mediated by ATP-Dependent Transporters: A New Hope
for Patient with Tumors Resistant to Conventional Chemotherapy
Pp. 886-903
C. Barthomeuf, M.-L. Bourguet-Kondracki
and J.-M. Kornprobst
[Abstract] [Purchase
Article]
Chemical and Clinical Development of Darinaparsin,
a Novel Organic Arsenic Derivative Pp. 904-909
A. Quintás-Cardama, S. Verstovsek, E.
Freireich, H. Kantarjian, Y.W. Chen and R. Zingaro
[Abstract] [Purchase
Article]
Analogues of Marine Pyrroloiminoquinone Alkaloids: Synthesis
and Antitumor Properties Pp. 910-916
E. Delfourne
[Abstract] [Purchase
Article]
Autotaxin Inhibition: Challenges and Progress Toward
Novel Anti-Cancer Agents Pp. 917-923
A.L. Parrill and D.L. Baker
[Abstract] [Purchase
Article]
Abstracts
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Editorial:
The fight against cancer progresses regularly
with continuous efforts on prevention, diagnostic, surgery,
chemo- and radiotherapy. Nevertheless, the cancer disease
still remains a leading life-threatening pathology in a large
number of indications. In that sense, there is still a huge
need for novel therapeutic strategies. Based on the increasing
knowledge of the biology of the cancer(s), novel original
strategies to treat cancer patients emerge day after day.
In this special issue, we are covering one of these new targets:
CDC25 phosphatase, with all the latest and outstanding developments
in research supporting that CDC25 phosphatase would be a novel
therapeutic target against cancer.
Briefly, the name CDC25 is coming from Cell division cycle
25 (CDC25) and is represented by three family members in the
human genome: CDC25A, CDC25B and CDC25C which are all key
actors in eukaryotic cell cycle control. They are responsible
for the dephosphorylations that activate the cyclin-dependent
kinases (CDK) at specific stages of the cell cycle and also
central regulators of the G2/M checkpoint mechanisms activated
in response to DNA injury. The expression and activity of
these enzymes are finely regulated by multiple mechanisms
including post-translational modifications, interactions with
regulatory partners, control of their intracellular localization,
and cell cycle-regulated degradation (see review Bernadette
Aressy and Bernard Ducommun). The specific role for each of
these three proteins is still under investigation showing
both different and redundant specificities and regulations
not shared by all the members (see review Anne Fernandez-Vidal,
Anne Mazars, & Stephane Manenti). Altered expression of
these phosphatases is associated with checkpoint bypass and
genetic instability. Accordingly, increased expressions of
CDC25 (A, B & C) are found in many high-grade tumors and
are frequently correlated with poor prognosis in human cancers.
Studies using mouse models demonstrated that deregulated expression
of CDC25A significantly promotes RAS- or NEU-induced mammary
tumor development with chromosomal aberrations, whereas decreased
CDC25A expression in heterozygous knockout mice delays tumorigenesis.
These biological properties of CDC25 phosphatases provide
significant insight into the pathobiology of cancer and scientific
foundation for anti-CDC25 therapeutic intervention (see review:
Hiroaki Kiyokawa and Dipankar Ray). These protein tyrosine
phosphatases are therefore recognized as attractive molecular
targets for small molecules. Consequently, challenges for
developing small molecule inhibitors of the Cdc25 family and
a number of potential chemical probes are discussed and their
characteristics are summarized (see review: John S. Lazo and
Peter Wipf; M-C. Brezak et al.; A. Lavecchia et
al.). Finally, one key example of preclinical studies
using a CDC25 inhibitor has been presented by the group of
B. Carr (see review: Ziqiu Wang, Siddhartha Kar & Brian
I. Carr) which may provide new means to control cancers of
the liver and other sites.
All the papers associated in this book describe an increasing
body of evidence on the role of CDC25 in cancer progression.
All these reviews cover complementary aspects of CDC25: the
role of CDC25s in the normal cell and during the tumorigenesis,
the consideration of CDC25 as a relevant druggable target,
the discovery of new cdc25 inhibitors and finally the preclinical
approaches. Such a special issue will allow every one who
wishes to be informed and updated with the latest and most
important developments in the CDC25 field.
Dr. Grégoire Pierre Prevost
Director
Oncology Research, IPSEN
5 avenue du Canada
91966 Les Ulis
France
Tel: 33 01 60 92 20 69
Fax: 33 01 69 07 38 02
E-mail: gregoire.prevost@ipsen.com
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Article]
Cell Cycle Control by the CDC25 Phosphatases
B. Aressy and B. Ducommun
Cell division cycle 25 (CDC25) phosphatases are key actors
in eukaryotic cell cycle control. They are responsible for
the dephosphorylations that activate the cyclin-dependent
kinases (CDK) at specific stages of the cell cycle. Human
CDC25A, CDC25B and CDC25C are also central targets and regulators
of the G2/M checkpoint mechanisms activated in response to
DNA injury. The expression and activity of these enzymes is
finely regulated by multiple mechanisms including post-translational
modifications, interactions with regulatory partners, control
of their intracellular localization, and cell cycle-regulated
degradation. Altered expression of these phosphatases is associated
with checkpoint bypass and genetic instability. Accordingly,
increased expression of CDC25A and CDC25B is found in many
high-grade tumors and is correlated with poor prognosis in
human cancers. This review summarizes our current knowledge
within this domain and discusses the data that support therapeutic
strategies targeting CDC25 activity in the treatment of cancer.
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Article]
CDC25A: A Rebel Within the CDC25 Phosphatases Family?
A. Fernandez-Vidal, A. Mazars and S.
Manenti
CDC25 dual specificity phosphatases activate the cyclin-dependent
kinase complexes, allowing timely ordered progression through
out the different phases of the eukaryotic cell cycle. In
humans, there are three genes coding for the CDC25A, B and
C proteins with both different and redundant specificities
and regulations. The CDC25A member of this family acts during
the G1 phase and at the G1/S transition by activating the
CDK2/cyclin E and CDK2/cyclin A complexes, a function apparently
not shared by the other members. In consequence, CDC25A is
submitted to extra-cellular signals-dependent regulations
involving in particular mitogenic signal transducers, and
leading to modifications of its stability, its localization
or its activity. In addition, CDC25A is up-regulated in various
cancers, and the molecular mechanisms leading to this up-regulation
are far from being understood. In this review, we will synthesize
the current knowledge about CDC25A molecular regulations,
and try to integrate these data in the cell proliferation
and apoptotic functions described for the protein.
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In Vivo Roles of CDC25 Phosphatases:
Biological Insight into the Anti-Cancer Therapeutic Targets
H. Kiyokawa and D. Ray
CDC25 phosphatases are not only rate-limiting activators
of cyclin-dependent kinases (CDKs) but also important targets
of the CHK1/CHK2-mediated checkpoint pathway. Each isoform
of the mammalian CDC25 family seems to exert unique biological
functions. CDC25A is a critical regulator for both G1-S and
G2-M transitions and essential for embryonic cell proliferation
after the blastocyst stage. CDC25B is dispensable for embryogenesis
but required for meiotic progression of oocytes in a manner
analogous to Drosophila Twine or C. elegans cdc-25.1.
Moreover, CDC25A and CDC25B appear to regulate different events
or stages of mitosis. CDC25B may mediate the activation of
CDK1/Cyclin B at the centrosome during prophase, while CDC25A
may be required for the subsequent full activation of nuclear
CDK1/Cyclin B. CDC25C is dispensable for both mitotic and
meiotic divisions, although it is highly regulated during
the processes. Excessive levels of CDC25A and CDC25B are often
observed in various human cancer tissues. Deregulated expression
of these phosphatases allows cells to overcome DNA damage-induced
checkpoint, leading to genomic instability. Studies using
mouse models demonstrated that deregulated expression of CDC25A
significantly promotes RAS- or NEU-induced mammary tumor development
with chromosomal aberrations, whereas decreased CDC25A expression
in heterozygous knockout mice delays tumorigenesis. These
biological properties of CDC25 phosphatases provide significant
insight into the pathobiology of cancer and scientific foundation
for anti-CDC25 therapeutic intervention.
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Article]
Is Cdc25 a Druggable Target?
J.S. Lazo and P. Wipf
Proper control of cell cycle progression requires the
functionality of a small family of activating phosphatases
termed Cdc25, which have been implicated in cancer and Alzheimer’s
disease. These protein tyrosine phosphatases are therefore
recognized as attractive molecular targets for small molecules.
We review the rationale, approaches, progress and challenges
for developing small molecule inhibitors of the Cdc25 family.
A number of potential chemical probes are discussed and their
characteristics are summarized.
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Article]
Cdc25B Phosphatase Inhibitors in Cancer Therapy: Latest Developments,
Trends and Medicinal Chemistry Perspective
A. Lavecchia, A. Coluccia, C. Di Giovanni
and E. Novellino
The Cdc25 phosphatases (Cdc25A, Cdc25B, and Cdc25C in
humans), which are responsible for dephosphorylating specific
tyrosine/threonine residues on cyclin dependent kinases (CDKs),
function as essential regulators of cell cycle control during
normal eukaryotic cell division and as mediators of the checkpoint
response in cells with DNA damage. Because overexpression
of Cdc25A and Cdc25B has been linked to numerous cancers and
often correlates with a poor clinical outcome, both academia
and industry have devoted substantial research effort in establishing
the basic underlying molecular mechanisms and in identifying
novel, specific and potentially useful inhibitors of Cdc25
as potential anticancer drugs. Over the past year, dozens
of research papers and patent applications describing new
Cdc25 inhibitors belonging to different structural classes
have been disclosed. In this review, we give an overview on
the current status in the field of medicinal chemistry of
Cdc25B inhibitors. In addition, molecular modeling studies
aimed to clarify the molecular mechanism of inhibition as
well as the pharmacophoric features critical for design of
new and selective Cdc25B inhibitors are also discussed.
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CDC25 Inhibitors as Anticancer Agents Are Moving Forward
M.-C. Brezak, P.G. Kasprzyk, M.-O. Galcera,
O. Lavergne and G. P. Prévost
The identification of a CDC25 inhibitor to arrest the
cell cycle closely followed the discovery of CDC25 by Russell
and Nurse in 1986. Recent advances at the preclinical and
clinical stages reinforce the rationale to consider CDC25
as a relevant target for a cancer treatment. Here, in order
to exemplify recent drug discovery efforts, we present our
own experience with various chemical series of CDC25 inhibitors.
We discuss how we have progressed and how we are considering
the next steps to define the clinical entry points and hopefully
complete this target validation to generate a new class of
therapeutic agents.
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Cdc25A Protein Phosphatase: A Therapeutic Target for Liver
Cancer Therapies
Z. Wang, S. Kar and B.I. Carr
Cdc25A, a dual specificity protein phosphatase, is well-recognized
as a critical regulator for cell cycle progression. We recently
found that it also regulates mitogen-activated protein kinase
(MAPK) signal transduction pathway. Inhibition of Cdc25A activity
by a K vitamin analog Compound 5 (Cpd 5) can induce a strong
and prolonged activation of epidermal growth factor receptor
(EGFR)-MAPK pathway, which leads to suppression of transcription
factors CREB and c-Myc, resulting in decreased expression
of Cdc25A and cyclin D1 levels. Our investigations suggest
that Cdc25A plays a central role in regulating and linking
cell cycle progression and MAPK signal transduction pathways.
Several other recently synthesized K vitamin analogs also
affect this pathway, including the non-quinone PM20 and fluoro-Cpd
5. Thus, searching for new and efficient small molecules to
inhibit Cdc25A activity may provide new means to control cancers
of the liver and other sites.
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Proliferation of Breast Cancer Cells: Regulation, Mediators,
Targets for Therapy
J. Mester and G. Redeuilh
A majority of breast cancers (BC) display characteristics
of epithelial cells and express estrogen receptors and/or
HER-2 (a member of the epidermal growth factor receptor family).
About one-fifth of BC is constituted of basal cells for which
there is no specific category of proliferation regulators.
Insulin-like growth factor (IGF) signaling is involved in
most BC cells, irrespective of cell type.
All inducers of cell proliferation employ transcriptional
as well as non-transcriptional mechanisms to activate the
cascade of cyclin-dependent kinases, which causes irreversible
progression to the G1/S phase transition. We analyze the pathways
of the different inducers that lead to this cascade. Several
actors in the mitogenic signal transduction are required irrespective
of the initial signal although their functions may differ:
for example members of the mitogen-activated protein kinase
(MAPK) and phosphatidylinositol-3 kinase (PI3K) cascades.
As some of these proteins are also involved in the cell survival
mechanisms, they appear to be good targets for therapeutic
intervention. In the case of the estrogen-dependent cells,
complex interplay between the estrogen receptor (a conditional
transcription factor), co-repressors and co-activators offers
additional molecular targets for therapy. Besides, we have
found that p21WAF1, an inhibitor
of cyclin-dependent kinases, can orient the cell to either
proliferation or differentiation suggesting that at an early
stage of BC development it may be possible to reverse the
cellular changes associated with malignant transformation.
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Marine Metabolites Overcoming or Circumventing Multidrug Resistance
Mediated by ATP-Dependent Transporters: A New Hope for Patient
with Tumors Resistant to Conventional Chemotherapy
C. Barthomeuf, M.-L. Bourguet-Kondracki
and J.-M. Kornprobst
The treatment of chemoresistant tumors represents an
important challenge in the field of oncology. Primary or acquired
overexpression of ATP-dependent transporters, in particular
P-glycoprotein (Pgp, MDR1 protein), is a major cause of multidrug
resistance and reduced patient survival. Sustained efforts
have thereby been undertaken to find agents overcoming this
resistance. This review provides a chemical and biological
overview on bioactive metabolites from the marine field (natural
molecules and analogues) that can overcome or circumvent resistance
to ATP-dependent efflux pumps, their mechanisms of action
and their structure-activity relationships. Their clinical
relevance and status are presented. Active compounds (often
microtubule-interacting agents) have been isolated from sponges
and ascidians and, in lesser extent from cnidarians, and molluscs.
The toxicity and the reversal activity can be uncoupled but,
marine metabolites usually maintain high toxicity in multiresistant
cancer cells. Certain display synergistic effects with clinically
important anticancer drugs. The marine drug recently approved
for cancer therapy [Trabectedin (Yondelis®)]
and those entered into clinical trials act on multiple targets
and, circumvent or overcome chemoresistance through very unusual
mechanisms of action. Pharmacological and clinical data suggest
that metabolites from the marine field could provide new therapeutic
options for patients with tumors resistant to conventional
therapy.
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Chemical and Clinical Development of Darinaparsin, a Novel
Organic Arsenic Derivative
A. Quintás-Cardama, S. Verstovsek, E.
Freireich, H. Kantarjian, Y.W. Chen and R. Zingaro
The inorganic arsenic derivative arsenic trioxide (ATO)
has proven to be highly efficacious in patients with acute
promyelocytic leukemia (APL) and has been associated with
complete cytogenetic response in most treated patients diagnosed
with this disease. This is due to ATO’s direct effect
on PML-RARα
oncoprotein patognomonic for APL. ATO has shown moderate
activity against certain other hematologic and solid organ
malignancies but is also associated with significant toxicities,
especially when used at higher doses. The development of orally
bioavailable organic arsenic derivatives (OAD) offering improved
toxicity profiles and better efficacy may expand the use of
arsenic derivatives in hematologic malignancies and solid
tumors.
The favorable in vivo carcinostatic activity of S-dimethylarsino-thioglucose,
the first OAD synthesized in murine leukemia models by our
group in 1975, set the stage for our efforts to develop OADs.
Unfortunately, the program remained dormant for almost two
decades. The success of ATO in APL in the late 1990s re-ignited
the interest in the use of OADs in cancer chemotherapy.
This review describes the chemical development of OADs and
summarizes the clinical development of a promising lead compound,
Darinaparsin (ZIO-101; SGLU; S-dimethylarsino-glutathione),
for the treatment of a variety of cancers.
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Analogues of Marine Pyrroloiminoquinone Alkaloids: Synthesis
and Antitumor Properties
E. Delfourne
Marine organisms provide a valuable source for natural
products. In recent years, iminoquinone alkaloids including
makaluvamines, isobatzellines, tsitsikammamines and wakayin,
have emerged as an essential class of marine metabolites due
to their prominent biological activities and unusual ring
structures. This review focuses on synthesis and antitumor
evaluation of analogues of these products.
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Autotaxin Inhibition: Challenges and Progress Toward Novel
Anti-Cancer Agents
A.L. Parrill and D.L. Baker
Autotaxin (ATX, autocrine motility factor, NPP2) has
recently emerged as an attractive target for the development
of anti-cancer chemotherapeutics. ATX contributes to the production
of the bioactive lipid, lysophosphatidic acid (LPA), from
lysophosphatidyl choline (LPC) in biological fluids including
plasma, serum, and tumor cell effusates. LPA-stimulated cell
proliferation, survival, motility and invasion have been demonstrated
by numerous research groups. LPA receptors and ATX are upregulated
in numerous cancer cell types and show expression patterns
that correlate with tumor cell invasiveness. Despite considerable
promise as an anti-cancer target, two complex challenges have
slowed inhibitor discovery. The first of these challenges
has been a lack of experimental details of the enzyme structure
and its interactions with substrates or inhibitors. A second
challenge has been a lack of structural diversity among initially
reported inhibitors. Research reported in the last two years
provides a foundation to begin addressing these challenges.
Although an experimental structure of ATX is not among these
recent developments, a crystal structure of the bacterial
enzyme Xac. NPP is now available. This protein shares
35% identity with the central catalytic domain of ATX and
provides an important starting point to begin understanding
the structure of ATX. The structural diversity of known inhibitors
has recently expanded to include not only phospholipid analogs,
but also small molecules containing thiourea, diphenyldiazerenyl,
anthracenedione and indole central cores. These two developments
are essential tools for the discovery and optimization of
ATX-targeted agents for evaluation as anti-cancer chemotherapeutic
agents.
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