| Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 9, Number 6, July 2009
Contents
Protein Targets in the Treatment
of Cancers
Guest Editor: Sabbir Ahmed
Editorial Pp. 598
Estrone Sulfatase and Its Inhibitors Pp.
599-612
K. Aidoo-Gyamfi, T. Cartledge, K. Shah and
S. Ahmed
[Abstract] [Purchase
Article] [PMID: 19601744 PubMed - indexed for MEDLINE]
17α-Hydroxylase/17,20-Lyase
(P45017α)
Inhibitors in the Treatment of Prostate Cancer: A Review
Pp. 613-626
C.P. Owen
[Abstract] [Purchase
Article] [PMID: 19601745 PubMed - indexed for MEDLINE]
Aromatase: The Enzyme and Its Inhibition
Pp.627-641
L. Banting and S. Ahmed
[Abstract] [Purchase
Article] [PMID: 19601746 PubMed - indexed for MEDLINE]
Advances in Development of Inhibitors
of 17β
Hydroxysteroid Dehydrogenases Pp. 642-660
D. Poirier
[Abstract] [Purchase
Article] [PMID: 19601747 PubMed - indexed for MEDLINE]
Histone Deacetylase Inhibitors: Design,
Structure-Activity Relationships and Therapeutic Implications
for Cancer Pp. 661-692
C.M. Marson
[Abstract] [Purchase
Article] [PMID: 19601748 PubMed - indexed for MEDLINE]
Inhibition of Carbonic Anhydrase IX:
A New Strategy Against Cancer Pp. 693-702
J.-Y. Winum, A. Scozzafava, J.-L. Montero
and C.T. Supuran
[Abstract] [Purchase
Article] [PMID: 19601749 PubMed - indexed for MEDLINE]
The Epidermal Growth Factor Receptor
as a Therapeutic Target in Glioblastoma Multiforme and other
Malignant Neoplasms Pp. 703-715
S. Loew, U. Schmidt, A. Unterberg and M.-E.
Halatsch
[Abstract] [Purchase
Article] [PMID: 19601750 PubMed - indexed for MEDLINE]
Abstracts
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Editorial
The use of compounds to affect the activity of proteins
(both enzymes and receptors) is still under extensive consideration
in the development of novel anti-tumour agents. In this issue,
we consider a number of targets which have been (and continue
to be) under investigation and which have shown therapeutic/clinical
potential in the treatment of cancers. However, due to the
nature of the area, it is difficult to undertake an extensive
coverage of the use of small molecules against proteins within
a journal issue, as such, the authors have attempted to provide
the reader with a background into the general approach in
the treatment of cancers through the use of protein modulators.
The first paper by Aidoo-Gyamfi et al. covers one
of the novel areas which have been shown to have clinical
potential, namely the use of inhibitors of estrone sulfatase
in the treatment of hormone-dependent breast cancer. The paper
gives an overview of the area as well as discussing some compounds
(for example, STX-213) which possess the potential to enter
the clinic. The paper by Owen discusses another enzyme target
within the steroidal cascade, namely, 17α-hydroxylase/17,
20-lyase, which has mainly been targeted in the treatment
of androgen-dependent prostate cancer. A number of compounds
have been targeted at this enzyme which has shown real potential,
for example, abiraterone acetate has shown real promise in
clinical trials, in particular, against refractory prostate
cancer. This enzyme also has potential use in the treatment
of estrogen-dependent breast cancer since it is a pivotal
enzyme in the biosynthesis of the sex steroids. Indeed, 17α-hydroxylase/17,
20-lyase results in the biosynthesis of androgens which can
therefore lead, via the action of the enzyme aromatase,
to the biosynthesis of estrogens, the topic of the third paper
by Banting and Ahmed. This paper therefore covers an enzyme
which has shown real clinical significance through the emergence
of drugs such as anastrozole and letrozole in the treatment
of estrogen-dependent breast cancer. In his paper, Poirier
discusses the inhibition of the enzyme 17β-hydroxysteroid
dehydrogenase as this family of enzymes is involved in the
transformation of weaker steroids (for example androstenedione
or estrone) into the more potent sex steroids (for example
testosterone and estradiol respectively) and vice versa. This
enzyme has only recently become of importance since it was
previously assumed to be a weak target due to non-specificity
of the compounds since there are some 15 types of this enzyme
which have been reported to exist. However, as discussed,
a number of compounds have been shown to possess specificity
and this enzyme has become a major target in the treatment
of both hormone-dependent breast and prostate cancers. As
such, these four papers represent the majority of the efforts
directed towards the disruption of the steroidal cascade and
therefore the treatment of hormone-dependent cancers. In the
paper by Marson, the targeting of histone deacetylase is discussed
with an overview of the different types of compound used to
target this enzyme; the paper also discusses the potential
use of inhibitors of this enzyme against refractory cancer.
The paper by Winum et al. gives an extensive overview
of the use of inhibitors against carbonic anhydrase, in particular,
against isozyme IX of carbonic anhydrase. This isozyme has
been implicated in the control of cell proliferation and cellular
malignant transformation, indeed; its expression has been
shown to be restricted in normal tissues but has been closely
associated with different types of tumours, especially hypoxic
solid tumours. Finally, Loew et al. discuss the targeting
of epidermal growth factor receptor since it has been shown
to be dysregulated in various tumour types including breast
cancer and glioblastoma multiforme (GBM). In particular, treatments
against GBM are discussed; a disease which is associated with
a median survival of only 40 to 60 weeks from diagnosis, as
such, this paper gives an insight into the achievements and
challenges associated in the treatment of GBM.
I believe, therefore, that this special issue will successfully
introduce the reader to the challenges and achievements associated
with a small number of targets which are under consideration
in the treatment of various cancers.
Sabbir Ahmed
Guest Editor
Anti-Cancer Agents in Medicinal Chemistry
Head of School of Science
School of Science
University of the West of Scotland
Paisley, Scotland
PA1 2BE
United Kingdom
Tel: 0141-848-3000
E-mail: sabbir.ahmed@uws.ac.uk
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[Purchase
Article] [PMID: 19601744 PubMed - indexed for MEDLINE]
Estrone Sulfatase and Its Inhibitors
K. Aidoo-Gyamfi, T. Cartledge, K. Shah and
S. Ahmed
A high proportion (~40%) of breast cancers are hormone-dependent
and it is the female hormone estradiol (E2) that is believed
to play a key role in the initiation, promotion and progression
of this disease. In the fight against this disease, compounds
which are potent inhibitors of the cytochrome P-450 enzyme
aromatase (AR) (which catalyses the conversion of the C19
androgens to the C18 estrogens)
have been the major target. However, the administration of
AR inhibitors alone does not prevent the localised biosynthesis
of estrone (E1) (and therefore the subsequent synthesis of
E2) within breast tumour cells via alternative non-AR routes.
This has therefore been the major impetus for the development
of steroid sulfatase (E1STS) inhibitors. The E1STS enzyme
regulates the formation of E1 from estrone sulfate (E1S),
a steroid conjugate present in high concentrations in tissue
and blood in women with breast cancer. The STS enzyme has
also been shown to catalyse the formation of dehydroepiandrosterone
(DHEA) from DHEA-sulfate (DHEAS). This is important since
DHEA can be converted to 5-androstene-3β,17β-diol,
which has been shown to possess weak estrogenic properties,
however, due to the high concentration of this steroid, it
is able to stimulate the growth of breast cancer cells in
vitro and in vivo. Considerable progress has
been made in recent years in the development of a number of
potent E1STS inhibitors, as such both steroidal and non-steroidal
compounds have been considered and a number of highly potent
inhibitors have been produced and evaluated against what is
now considered a crucial enzyme in the fight against hormone-dependent
breast cancer. The review therefore summarises the work that
has been undertaken todate.
[Back to top]
[Purchase
Article] [PMID: 19601745 PubMed - indexed for MEDLINE]
17α-Hydroxylase/17,20-Lyase
(P45017α)
Inhibitors in the Treatment of Prostate Cancer: A Review
C.P. Owen
Prostate cancer is an age-related disease and a major
cause of death in Western countries. A large proportion of
prostate cancers have been found to be dependent on androgens
for growth and various therapeutic approaches have aimed at
either decreasing androgen levels or blocking their action.
One method of decreasing androgen levels is through inhibition
of enzymes involved in the biosynthetic pathway, for example,
the P450 enzyme complex 17α-hydroxylase/C17,20-lyase
(P45017α),
which catalyses the conversion of pregnenolone and progesterone
into the androgen precursors dehydroepiandrosterone and androstenedione
respectively. A number of researchers have targeted this enzyme
and have produced potent steroidal and non-steroidal inhibitors.
This review looks at the various inhibitors that have been
developed, focussing mainly on more recent inhibitors reported
over the last ten years. Some mention is also given to structural
requirements suggested to be important for potent activity.
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[Purchase
Article] [PMID: 19601746 PubMed - indexed for MEDLINE]
Aromatase: The Enzyme and Its Inhibition
L. Banting and S. Ahmed
The genetic control, mechanism of action and inhibition
of aromatase for potential therapeutic benefits in the arena
of hormone dependent illness continues to be of considerable
interest. The work presented here concentrates on recent advances
in the mechanistic aspects of the aromatase enzyme and the
nature of the chemical entities that lead to its inhibition.
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[Purchase
Article] [PMID: 19601747 PubMed - indexed for MEDLINE]
Advances in Development of Inhibitors of 17β
Hydroxysteroid Dehydrogenases
D. Poirier
The 17β-hydroxysteroid
dehydrogenases (17β-HSDs)
are involved in the regulation of estrogens and androgens
by catalyzing the reduction of 17-ketosteroids or the oxidation
of 17β
hydroxysteroids. The enzyme activities associated with the
different 17β-HSD
isoforms are widespread in human tissues, not only in classic
steroidogenic tissues but also in a large series of peripheral
intracrine tissues. Being involved at the end of steroidogenesis,
the numerous members of 17β-HSD
family constitute interesting therapeutic targets for controlling
the concentration of estrogens and androgens. Thus, inhibitors
of reductive 17β-HSD
isoforms are attractive to block the formation of hydroxysteroids
that stimulate estrogeno-sensitive pathologies (breast, ovarian,
and endometrium cancers) and androgeno-sensitive pathologies
(prostate cancer, benign prostatic hyperplasia, acne, and
hirsutism). The inhibitors could be used to block the degradation
of estradiol, an attractive strategy for treating osteoporosis
and Alzheimer’s disease. In addition to their classical
use as anti-cancer agents and therapeutic agents, inhibitors
of 17β-HSDs
are also useful tools to elucidate the role of these enzymes
in particular biological systems. The present review article
gives a description of novel inhibitors of 17β-HSDs
that were published in 2003-2006.
[Back to top]
[Purchase
Article] [PMID: 19601748 PubMed - indexed for MEDLINE]
Histone Deacetylase Inhibitors: Design, Structure-Activity
Relationships and Therapeutic Implications for Cancer
C.M. Marson
Histone deacetylases (HDACs) remove acetyl groups
from the tails of lysine residues of histone protein in nuclear
chromatin and also from acetylated sites in non-histone proteins.
HDACs and histone acetyltransferases (HATs) are major influences
on the level of cellular protein acetylation, and an imbalance
in acetylation levels, particularly under-acetylated (hypoacetylated)
histone protein has been associated with precancerous or malignant
states. Consequently, small molecule inhibitors of HDACs have
been synthesised and some now form a newly emerging class
of anti-cancer agents that can regulate transcription and
inhibit proliferation of cancer cells by inducing cell cycle
arrest, differentiation and/or apoptosis, among other major
biological phenomena. The different mechanism(s) of action
of HDAC inhibitors compared to conventional anti-neoplastic
agents provides a possibility that HDAC inhibitors may be
effective for refractory cancers. Accordingly, a number of
programs for the development of HDAC inhibitors as anti-cancer
drugs have been initiated. This review highlights recent developments
in the design, synthesis and biological properties of HDAC
inhibitors in the context of potential cancer therapy.
[Back to top]
[Purchase
Article] [PMID: 19601749 PubMed - indexed for MEDLINE]
Inhibition of Carbonic Anhydrase IX: A New Strategy Against
Cancer
J.-Y. Winum, A. Scozzafava, J.-L. Montero
and C.T. Supuran
Of the thirteen active carbonic anhydrase (CA) isozymes,
the transmembrane isoform CA IX has been shown to be linked
with carcinogenesis. CA IX presents an ectopic expression
in a multitude of carcinomas derived from cervix, uteri, kidney,
lung, oesophagus, breast, colon, etc., contrasting with its
restricted expression in normal tissues, namely in the epithelia
of the gastrointestinal tract. It has been demonstrated that
this membrane-bound CA is strongly overexpressed in hypoxic
tumors, participating in tumor cell environment acidosis and
contributing to malignant progression and poor treatment outcome.
Targeting CA IX could thus be an important means of controlling
cancer disease. Modulation of extracellular tumor pH via
inhibition of CA IX activity represents a promising approach
to novel anticancer therapies. Much attention has recently
been paid to the CA IX inhibitors drug design, and efforts
have been made to obtain isozyme IX inhibitors, with putative
applications as antitumor drugs/diagnostic agents. This review
will focus on the different CA IX inhibitors described in
the literature which could represent excellent potential as
candidate therapeutic agents in cancer chemotherapy.
[Back to top]
[Purchase
Article] [PMID: 19601750 PubMed - indexed for MEDLINE]
The Epidermal Growth Factor Receptor as a Therapeutic Target
in Glioblastoma Multiforme and other Malignant Neoplasms
S. Loew, U. Schmidt, A. Unterberg and M.-E.
Halatsch
The epidermal growth factor receptor (EGFR) is dysregulated
in various tumour types such as glioblastoma multiforme (GBM),
breast cancer, ovarian carcinoma, non-small cell lung cancer
and other cancers. As the intracellular tyrosine kinase of
the EGFR activates signalling cascades leading to cell proliferation,
angiogenesis and inhibition of apoptosis, the EGFR represents
an attractive target in cancer therapy. In GBM which is the
most common primary central nervous system tumour in adults,
the EGFR is overexpressed in about 40 to 50% of cases, and
almost half of these co-express the mutant receptor subtype
EGFRvIII. This EGFR variant is constitutively activated, and
thereby may contribute to the aggressive and refractory course
of GBM which is associated with a median survival of only
40 to 60 weeks from diagnosis. Various trials are ongoing
focusing on EGFR and EGFRvIII as new therapeutic targets in
GBM. Anti-EGFR monoclonal antibodies (MAbs), e.g. cetuximab,
and tyrosine kinase inhibitors (TKIs), e.g. erlotinib and
gefitinib, are the most advanced in clinical development.
Several trials are investigating MAbs or TKIs in combination
with other agents such as inhibitors of the mammalian target
of rapamycin. Other still preliminary approaches targeting
the EGFR are small interfering RNA, antisense RNA and ribozymes,
which lead to degradation of EGFR mRNA. Further studies
are needed to define their clinical potential, to identify
biological predictors of response and thus to characterize
subgroups of patients who will benefit from treatment with
these new agents.
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