Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 6, Number 3, 2006
Contents
Nuclear Receptors as Targets in Drug Discovery:
Medicinal Chemistry and Therapeutic Potential
Guest Editor: Mary J. Meegan
Editorial Pp. 179
Estrogen Receptors as Therapeutic Targets in Breast Cancer
Pp. 181-202
Eric A. Ariazi, Jennifer L. Ariazi, Fernando
Cordera and V. Craig Jordan
[Abstract]
Estrogen-Related Receptors as Emerging Targets in
Cancer and Metabolic Disorders Pp. 203-215
Eric A. Ariazi and V. Craig Jordan
[Abstract]
Estrogen Receptors: Molecular Interactions, Virtual
Screening and Future Prospects Pp. 217-243
Andrew J.S. Knox, Mary J. Meegan and David G. Lloyd
[Abstract]
Selective Androgen Receptor Modulators in Drug Discovery:
Medicinal Chemistry and Therapeutic Potential
Pp. 245-270
Rodolfo Cadilla and Philip Turnbull
[Abstract]
How Much is Enough? Modulation of Dose-Response Curve
for Steroid Receptor-Regulated Gene Expression by Changing
Concentrations of Transcription Factor Pp. 271-285
S. Stoney Simons, Jr.
[Abstract]
Abstracts
[Back to top]
Editorial
Nuclear receptors have become an important focus of clinical
and pharmaceutical investigation as they represent targets
for many of the key lipophilic hormones such as steroids,
thyroxine and retinoic acid. These receptors include the Androgen
Receptor (AR), Estrogen Receptor (ER), Progesterone Receptor
(PR), Glucocorticoid receptor (GR), Peroxisome Proliferator-Activated
Receptor (PPAR), Thyroid Receptor (TR), Vitamin D Receptor
and the various Steroid Receptor associated proteins (SRAPR).
These receptors function as ligand dependent transcriptional
regulators and are involved in the regulation of many critical
biochemical processes such as cell differentiation, development
and proliferation. The understanding of the complex chemical
structure and biochemical function of the nuclear receptor
family has expanded considerably in recent years in the areas
of hormonal signal transduction pathways and elucidation of
the molecular mechanisms by which gene activity is directly
regulated by the hormone receptor complex. The review topics
highlight the central role of the estrogen receptor (ER) as
a target in breast cancer including the development of acquired
resistance to exhaustive use of endocrine therapy and the
mechanism of endocrine based therapy resistance. The Estrogen-related
Receptors (ERR) are now recognized as potential therapeutic
targets and clinical markers in breast cancer.
Identification of the Estrogen Receptor (ER) as a key mediator
of the proliferation of breast cancer together with recognition
of its involvement in pathways leading to osteoporosis and
coronary heart disease, has resulted in the discovery and
design of compounds with the ability to modulate its actions
(SERMs). The recent phenomenal growth in potential new molecular
targets, together with automation, miniaturisation and combinatorial
chemistry have resulted in a huge increase in the number of
compounds available for conventional high throughput screening
(HTS). The possibilities for modulation of biochemical pathways
involving the ER are diverse and application of computational
techniques to a number of new targets may assist in the discovery
of compounds that could activate subsets of the ER pathway.
Modulation of the androgen receptor (AR) has the potential
to be an effective treatment for hypogonadism, andropause,
and associated conditions such as sarcopenia, osteoporosis,
benign prostatic hyperplasia, and sexual dysfunction. Side
effects associated with classical anabolic steroid treatments
have driven the quest for drugs that demonstrate improved
therapeutic profiles. Novel, non-steroidal compounds that
show tissue selective activity and improved pharmacokinetic
properties have been developed. An overview of current advances
in the development of selective androgen receptor modulators
(SARMs) provides an indication of the therapeutic potential
of these ligands.
Determination of the appropriate clinical dose of a steroid
drug to be both therapeutically effective and to avoid the
undersirable side effects is a complex problem due to interacting
factors and systems. However, approaches towards the prediction
of EC50 values for steroid induction of specific
genes should lead to specificy in clinical treatment.
The nuclear receptor family are clearly recognized as major
therapeutic targets for the development of new pharmaceutical
agents that can be useful for the treatment of hormone dependent
neoplasias and related diseased states.
Dr. Mary J. Meegan
School of Pharmacy and
Pharmaceutical Sciences
Trinity College Dublin,
Ireland
[Back to top]
Estrogen Receptors as Therapeutic Targets in Breast
Cancer
Eric A. Ariazi, Jennifer L. Ariazi, Fernando
Cordera and V. Craig Jordan
The estrogen receptor α
(ERα
) has proven to be the single most important target
in breast cancer over the last 30 years. The use of the selective
ER modulator (SERM) tamoxifen for the treatment and prevention
of breast cancer has changed therapeutics. The SERM raloxifene,
approved for the treatment of osteoporosis, lacks tamoxifen’s
increased risk for endometrial cancer and is being evaluated
for the prevention of breast cancer. Other SERMs approved
or under development for use against breast cancer or osteoporosis
include toremifene, GW5638, GW7604 (the active metabolite
of GW5638), idoxifene, lasofoxifene, arzoxifene, bazedoxifene,
EM-800 and acolbifene (the active metabolite of EM-800). Aromatase
inhibitors (AIs) have recently proven to be more efficacious
than tamoxifen as first-line therapy, efficacious for second-line
therapy (e.g. against tamoxifen-resistant disease),
and useful for extended adjuvant therapy after tamoxifen.
The AIs include the non-steroidal agents letrozole and anastrole,
and the steroidal agent exemestane. The pure antiestrogen
fulvestrant has proven to be just as effective as AIs. Other
pure antiestrogens, ZK-703, ZK-253, RU 58668 and TAS-108 show
great promise. The development of resistance to endocrine
therapy remains a clinically important problem, and laboratory
models based on human breast cancer cells grown as tumors
in immune-compromised mice have led to important insights
into this problem. Progesterone receptor-negative status of
ER-positive breast cancers may reflect altered growth factor
receptor signaling, and helps to explain why this subclass
of tumors exhibits lower response rates to tamoxifen compared
to cancers typed progesterone receptor-positive. Crosstalk
among plasma membrane-localized ER, growth factor receptor
signaling, and nuclear-localized ER provide further insights
into antihormonal-resistant breast cancer.
[Back to top]
Estrogen-Related Receptors as Emerging Targets in
Cancer and Metabolic Disorders
Eric A. Ariazi and V. Craig Jordan
While estrogen receptor (ER)-targeted therapeutics have clearly
been a success in the treatment of breast cancer, the orphan
estrogen-related receptors (ERRs) represent novel targets
for future development. The ERRs, comprising ERRα
, ERRβ
and ERRγ,
bind and regulate transcription via estrogen response
elements (EREs) and extended ERE half-sites termed ERR response
elements (ERREs), but do not bind endogenous estrogens. The
emerging role of ERRα
and ERRγ
in modulating estrogen responsiveness, substituting for ER
activities, and serving as prognosticators in breast and other
cancers is providing an impetus for the identification of
compounds which target these proteins. Moreover, ERRα
plays a role in energy homeostasis and will likely be targeted
for the treatment of metabolic disorders. Multiple classes
of synthetic ligands have already been identified. The phytoestrogens
genistein, daidzein, biochanin A and 6,3’4’-tryhydroxyflavone
have been reported as ERRα
agonists. The phenolic acyl hydrazones GSK4716 and GSK9089
act as selective agonists of ERRβ
and ERRγ.
The organochlorine pesticides toxaphene and chlordane, and
the synthetic compound XCT790 antagonize ERRα.
The synthetic estrogen diethylstilbestrol antagonizes all
three ERRs. The selective estrogen receptor modulators 4-hydroxytamoxifen
and 4-hydroxytoremifene antagonize ERRγ.
The rational development of synthetic ligands for the ERRs
may soon provide new agents to supplement the repertoire of
antihormonal therapies to combat breast cancer. Moreover,
expression of ERRs in other cancers and metabolic disorders
may provide a targeted treatment strategy for these patients
as well.
[Back to top]
Estrogen Receptors: Molecular Interactions, Virtual
Screening and Future Prospects
Andrew J.S. Knox, Mary J. Meegan and David G. Lloyd
Identification of the Estrogen Receptor (ER) as a key
mediator of the proliferation of breast cancer, and its involvement
in pathways leading to osteoporosis and coronary heart disease,
has resulted in a surge to discover and design compounds with
the ability to modulate its actions (SERMs). Concurrently,
a dramatic increase in the number of crystal structures of
the ER has led to a more in depth understanding of the governing
mechanisms involved in ER modulation. Entwining computational
techniques with the availability of 3D structural data, has
allowed not only the rational design of potent inhibitors
of the ER, but also its incorporation in Virtual Screening
(VS) in the search for novel chemotypes that can modulate
the ER.
An important initial step in the VS process is to filter towards
molecules that occupy similar chemical space to a set of known
actives prior to docking. We illustrate through Principal
Component Analysis (PCA) of 145 descriptors the region of
chemical space antiestrogens occupy compared with ‘drug-like’
space.
We also review all available studies involving validation
of several docking algorithms utilizing the ER, ultimately
focusing on analysis of Enrichment (E) rates and
False Positive (FP) rates to illustrate the successes attributed
to each docking algorithm.
Finally, we relate the recent discovery of non-genomic mechanisms
of the ER and subsequently present a model involving a recently
identified alternative, second binding-pocket of the ER in
our laboratory through cavity analysis that suggests how the
same receptor can invoke these, ‘classical’ and
rapid responses concurrently.
[Back to top]
Selective Androgen Receptor Modulators in Drug Discovery:
Medicinal Chemistry and Therapeutic Potential
Rodolfo Cadilla and Philip Turnbull
Modulation of the androgen receptor has the potential to
be an effective treatment for hypogonadism, andropause, and
associated conditions such as sarcopenia, osteoporosis, benign
prostatic hyperplasia, and sexual dysfunction. Side effects
associated with classical anabolic steroid treatments have
driven the quest for drugs that demonstrate improved therapeutic
profiles. Novel, non-steroidal compounds that show tissue
selective activity and improved pharmacokinetic properties
have been developed. This review provides an overview of current
advances in the development of selective androgen receptor
modulators (SARMs).
[Back to top]
How Much is Enough? Modulation of Dose-Response Curve
for Steroid Receptor-Regulated Gene Expression by Changing
Concentrations of Transcription Factor
S. Stoney Simons, Jr.
The position of the dose-response curve for steroid-regulated
gene expression determines how much variation in response
will accompany the normal physiological changes in circulating
steroid. Over the last several years, it has become clear
that the concentration of steroid hormone required for half-maximal
induction or repression by a given receptor-steroid complex,
which is normally called the EC50, is not constant
for all responsive genes. Thus, the position of the dose-response
curve can change so that a single concentration of steroid
produces very different percentages of maximal activity. This,
in turn, allows for the differential expression of genes by
a common steroid hormone concentration during development,
differentiation, and homeostasis. Here we review the variety
of factors that influence the EC50 and position
of the dose-response curve for steroid hormone receptors,
discuss what is known about the mechanisms, and highlight
promising areas for future research.
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