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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 2, 2009
Contents
Targeted Therapeutics –
From Chemical Structures to Diagnostic and Therapeutic Agents
Executive Editor: Christine Armbruster
Editorial: Pp. 118-119
Imatinib and Its Successors – How Modern Chemistry has
Changed Drug Development Pp. 120-133
B.A. Müller
[Abstract] [Purchase Article] [PMID: 19149608 PubMed - indexed for MEDLINE]
Chemoenzymatic Synthesis of Small Molecule Human Therapeutics
Pp. 134-152
N. Ran, E. Rui, J. Liu and J. Tao
[Abstract] [Purchase Article] [PMID: 19149609 PubMed - indexed for MEDLINE]
Targeted Drugs And Nanomedicine: Present And Future
Pp. 153-172
P. Debbage
[Abstract] [Purchase Article] [PMID: 19149610 PubMed - indexed for MEDLINE]
Nuclear Medicine: Proof of Principle for Targeted
Drugs in Diagnosis and Therapy Pp. 173-187
T. Leitha
[Abstract] [Purchase Article] [PMID: 19149611 PubMed - indexed for MEDLINE]
Targeted Therapies in Lung Cancer Pp. 188-206
R. Pirker and M. Filipits
[Abstract] [Purchase Article] [PMID: 19149612 PubMed - indexed for MEDLINE]
Targeted Therapies in Solid Tumours: Pinpointing the
Tumour’s Achilles Heel Pp. 207-242
G. Kornek and E. Selzer
[Abstract] [Purchase Article] [PMID: 19149613 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
Editorial: Targeted Therapeutics – From Chemical
Structures to Diagnostic and Therapeutic Agents
The first targeted therapeutic is presented by penicillin
that was discovered by Alexander Fleming in 1928. The first
radioactive-tracer experiments were performed as early as
in 1913 by Fritz Haber, Ernest Rutherford and George Charles
de Hevesy. The term “Magic bullet” was released
by Paul Ehrlich and refers to the concept of selectively targeting
a distinct bacterium without affecting other organisms. HIV
infection which was first described in 1981 led to tremendous
advances in drug design resulting in an effective therapeutic
agent five years after first description of the disease and
two years after identification of the infectious agent, the
Human Immunodeficiency Virus (HIV). Essential prerequisite
of drug design is the opportunity to perform high-resolution
structural analysis by means of structural biochemical procedures
as protein crystallography, nuclear magnetic resonance, and
computational biochemistry. Based on recent advances in discovering
enzymes through genome mining and metagenomics biocatalysis
is emerging as transformational technology for drug discovery
and production as will be presented by Ningqing Ran et
al. in this issue of “Current Pharmaceutical Design”.
Why do we need targeted drugs in diagnosis and treatment of
infectious diseases and cancer? The answer seems to be simple:
To enhance efficacy and to reduce harm of healthy tissue.
Are these aims achievable? In part: In case of HIV infection
targeted drugs as reverse transcriptase inhibitors (RTIs)
– the first-generation treatments of HIV-1 disease-
had only limited efficacy based on the interference of these
drugs with human cell metabolism. The HIV-1 protease emerged
as promising target and led to the development of protease
inhibitors (PIs) that are still one of the most effective
antiretroviral drugs. However, drug resistance and side effects
are major concerns. Recently approved compounds that attack
another target, the chemokine receptor CCR5 and the HIV-1
integrase demonstrated to have a more favorable safety profile.
In order to overcome the development of drug resistance agents
that are synergistic in action, that lack cross-resistance
and overlapping toxicity are combined representing the multi-drug
regimens that are commonly used in the treatment of HIV infection
[1].
As in HIV infection significant progress has been made in
the understanding of molecular mechanisms being involved in
cancer development and progression leading to similar steps
aiming at personalized therapy of cancer patients. Again some
concerns with respect to successful therapy are left: Firstly,
the molecular mechanisms leading to proliferation of malignant
cells and to tumor angiogenesis are complex. Secondly, cancer
cells overcome different growth factor signaling pathways
by using escape mechanisms for their growth and survival advantage.
Thirdly, drug resistance occurs based on mutational changes
within the target e.g. the tyrosine kinase as has been discussed
recently by Quintas-Gardama and Cortes [2]. Consequences are
on the one hand the design of compounds against these mutants
and on the other hand the combination of agents of the same
or different drug classes as multi-kinase inhibitors (e.g.
sorafenib), regimens consisting of Epidermal Growth Factor
Receptor (EGFR) and Vascular Endothelial Growth Factor (VEGF)
inhibitors as well as combining targeted drugs with conventional
chemotherapeutic agents (e.g. erlotinib, gemcitabine and cisplatin;
TALENT trial) [3]. Another approach is packaging drugs into
nanoparticles resulting in improved bio-availability, bio-compatibility
and safety profiles. Targeting particles can signal the presence
of the disease site, block a function there, and release a
drug to it as will be presented by Paul Debbage in this issue
of the journal. Targeting is desirable because many barriers
in human`s body hinder free access of the drug to its targets
as it is common knowledge for the blood brain barrier that
lowers the efficacy of therapies.
According to the “AIDS epidemic update” published
in December 2007 33.2 million people are living with HIV worldwide,
2.5 million have been newly infected in 2007, and 2.1 million
people died from AIDS in 2007 [4]. From the very beginning
of the AIDS epidemic treatment has dominated and prevention
strategies have been marginalized. But, treatment and prevention
are inextricable connected in HIV infection as well as in
cancer. Prevention in general needs to embrace political,
social, as well as economical determinants.
In comparison, 1,444,920 new cancer cases were projected in
2007 in the U.S., colorectal and lung cancer representing
the most frequent solid tumors in both women and men. However,
the U.S. cancer statistics give some hope since the incidence
rates of the most frequent solid tumors began to decline since
1992. In contrast a report studying 18 different cancer types
in 39 European countries demonstrated an increase from 2.4
million cancer cases in 2004 to 3.2 million in 2006 [5]. The
one side of the coin are global statistics the other side
is that successful prevention and treatment of solid tumors
require the acceptance that these are not single diseases
existing as a variety of phenotypes with different response
rates especially to targeted drugs. Present chemotherapy regimens
reached an efficacy plateau thus leading to the development
of targeted therapeutics. An important lesson learned is that
kinases are druggable targets for anti-cancer therapy leading
to about 90 encoded tyrosine kinases that are major players
in human cancers. Basically clinical benefit for patients
with cancer requires either improvement of overall survival
and of quality of life. Surrogate endpoints in clinical trials
should ideally be validated as a predictor of these parameters.
Very recently the discussion was raised if these surrogate
endpoints are appropriate in case of patients with metastatic
renal cell carcinoma. Furthermore ethical considerations arose
with respect to crossover in case of disease progression [6,
7]. Additionally to surrogate endpoints appropriate inclusion
criteria as well as patient and tumor characteristics that
might serve as predictors for treatment efficacy or failure
have to be defined.
This issue of the journal intends to draw a bow from lead
molecules being the basis of distinct drug classes to interdisciplinary
treatment concepts in oncology. Data are presented by chemists,
drug designers, physicians involved in basic science as well
as in the diagnostic and therapeutic approaches in patient
management.
The contributions of this issue are focusing on various subjects
in the field of oncology starting with the manuscript by B.A.
Mueller who describes the development of targeted drugs from
the chemists` point of view. Mueller travels through one century
of drug design finally dealing with drug resistance and novel
agents in the form of second and third generation tyrosine
kinase inhibitors used in the treatment of chronic myeloid
leukemia. Mueller gives insights in the essential work of
chemists in cooperation with pharmacists, crystallographers,
and clinicians.
The manuscript entitled “Chemoenzymatic Synthesis of
Small Molecule Human Therapeutics” by Ran and co-workers
provides interesting and important insights in drug development
and in the development of the pharmaceutical market focusing
on green chemistry. The design of a wide array of agents starting
with antibiotics as penicillin is described in an understandable
and concise manner. Historical backgrounds are given in the
same way as information with respect to the value of the agents
in terms of sale. Several steps between lead molecules and
registered agent are illustrated by perfect figures.
The document by P. Debbage covers an interesting topic that
of nanomedicine which is not common knowledge to clinicians.
Therefore Debbage`s contribution opens the eyes with respect
to the generalized use of nanomedicine in both diagnosis and
treatment. The achievements of nanomedicine have great impact
on diagnostic procedures in radiology and nuclear medicine.
Th. Leitha presents an amazing overview with respect to developments,
successes, and drawbacks in nuclear medicine. Leitha bends
a bow from nuclear medicine in the fields of in vitro
diagnostic tests over nuclear medicine in therapy to modern
diagnostic in vivo procedures as positron emissions
tomography (PET).
The last two contributions are dedicating in great parts the
successes and drawbacks in the management of patients with
different malignancies except hematological diseases that
are covered by Mueller in this issue.
R. Pirker and M. Filipits review established and investigational
treatment options in lung cancer. The focus of this paper
lies on recent advances in the treatment of non- small cell
lung cancer using EGFR inhibitors like cetuximab that have
been subject of a panel discussion during the last ASCO Meeting
in June 2008.
The management of solid tumors is covered by G. Kornek and
E. Selzer. More than three hundred references are listed giving
an extensive synopsis of the most recent developments in the
fields of interdisciplinary approaches e.g. in case of colorectal
cancer and of targeted drugs in this concert of treatment
options. The authors pay attention to multi-kinase inhibitors
that gained importance predominantly in the treatment of renal
cell carcinoma.
However, such concerted attempts to convert knowledge about
molecular mechanisms in oncogenesis into attractive treatment
concepts have just begun. An important experience is on the
one hand that kinases are druggable targets and on the other
hand that in the great majority of human cancers the two signaling
pathways that are controlled by the tumor suppressor genes
Rb and p53 are deregulated. There is some evidence that tumor
suppressor genes might be missing from the expressed genes
within cancer cells leading to a novel treatment concept that
of replacement of the missing tumor suppressor gene. Such
“gene therapies” would have the power to solve
the problem of cancer.
References
[1] Armbruster C. HIV infection: Recent developments in treatment
and current management strategies. Anti-Infect Agents Med
Chem 2008; 7: 201-14.
[2] Quintas-Gardama A, Cortes J. Therapeutic options against
BCR-ABL1 T315I-positive chronic myelogenous leukemia. Clin
Cancer Res 2008; 14: 4392-9.
[3] Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec
J, De Rosa F, et al. Phase III study of erlotinib
in combination with cisplatin and gemcitabine in advanced
non-small-cell lung cancer: the Tarceva Lung Cancer Investigation
Trial. J Clin Oncol 2007; 25: 1545-52.
[4] UNAIDS/WHO. AIDS Epidemic Update. Geneva, Switzerland:
UNAIDS/WHO, 2007, http://data.unaids.org/pub/EpiReport/2007/03
Introduction-2007_EpiUpdate_eng.pdf
[5] The Lancet. Cancer: some reasons to be hopeful. Lancet
2007; 369: 531.
[6] Knox J. Progression-free survival as endpoint in metastatic
RCC? Lancet 2008; 372: 427-8.
[7] Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda
S, et al; RECORD-1 Study Group. Efficacy of everolimus
in advanced renal cell carcinoma: a double-blind, randomised,
placebo-controlled phase III trial. Lancet 2008; 372: 449-56.
Christine Armbruster
Mantlergasse 23/2/12
A-1130 Vienna
Austria
Tel: +43 676 62 64 084
E-mail: christine.armbruster@gmx.at
[Back to top]
[Purchase Article] [PMID: 19149608 PubMed - indexed for MEDLINE]
Imatinib and Its Successors – How Modern Chemistry has
Changed Drug Development
B.A. Müller
Since protein kinases are frequently mutated or otherwise
deregulated in human malignancies, they serve as a target
for differentiating between tumor cells and normal tissues.
Imatinib mesylat (IM), an inhibitor of the BCR-ABL tyrosine
kinase was introduced in 2001 and has revolutionized the treatment
of patients with chronic myeloid leukemia (CML). Since 2005
a second generation of tyrosine kinase inhibitors is to follow
in Imatinib’s footsteps: The development of these new
small molecules was promoted by the identification of potential
target kinases within the cellular signaling apparatus. Modern
biochemical tools provide relevant amounts of these target
kinases necessary for high throughput screening (HTS) campaigns
and for elucidation of their 3-D structure by crystallography.
Supported by computational chemistry the resulting data have
enabled rational drug design.
In this review low molecular weight inhibitors used for the
CML treatment are summarized, pointing out their chemical
similarities and differences.
[Back to top]
[Purchase Article] [PMID: 19149609 PubMed - indexed for MEDLINE]
Chemoenzymatic Synthesis of Small Molecule Human Therapeutics
N. Ran, E. Rui, J. Liu and J. Tao
Pharmaceuticals have historically been produced by either
chemical synthesis or whole cell fermentation. The former
is applied to synthetic small molecules while the latter to
natural products. As a result of recent advances in rapid
discovery of enzymes through genome mining and metagenomics,
and their tunability in functions and stability through directed
evolution, biocatalysis is emerging to be a transformational
technology for drug discovery and production. Enzymes can
catalyze reactions otherwise challenging by chemical approaches.
Furthermore, enzymatic catalysis is a powerful tool for green
chemistry development. This manuscript gives a brief overview
of current status in integrating chemical and biological transformations
for the synthesis of small molecular therapeutics.
[Back to top]
[Purchase Article] [PMID: 19149610 PubMed - indexed for MEDLINE]
Targeted Drugs And Nanomedicine: Present And Future
P. Debbage
Packaging small-molecule drugs into nanoparticles improves
their bio-availability, bio-compatibility and safety profiles.
Multifunctional particles carrying large drug payloads for
targeted transport, immune evasion and favourable drug release
kinetics at the target site, require a certain minimum size
usually 30-300 nm diameter, so are nanoparticles. Targeting
particles to a disease site can signal the presence of the
disease site, block a function there, or deliver a drug to
it. Targeted nanocarriers must navigate through blood-tissue
barriers, varying in strength between organs and highest in
the brain, to reach target cells. They must enter target cells
to contact cytoplasmic targets; specific endocytotic and transcytotic
transport mechanisms can be used as trojan horses to ferry
nanoparticles across cellular barriers. Specific ligands to
cell surface receptors, antibodies and antibody fragments,
and aptamers can all access such transport mechanisms to ferry
nanoparticles to their targets. The pharmacokinetics and pharmacodynamics
of the targeted drug-bearing particle depend critically on
particle size, chemistry, surface charge and other parameters.
Particle types for targeting include liposomes, polymer and
protein nanoparticles, dendrimers, carbon-based nanoparticles
e.g. fullerenes, and others. Immunotargeting by use of monoclonal
antibodies, chimeric antibodies and humanized antibodies has
now reached the stage of clinical application. High-quality
targeting groups are emerging: antibody engineering enables
generation of human/like antibody (fragments) and facilitates
the search for clinically relevant biomarkers; conjugation
of nanocarriers to specific ligands and to aptamers enables
specific targeting with improved clinical efficacy. Future
developments depend on identification of clinically relevant
targets and on raising targeting efficiency of the multifunctional
nanocarriers.
[Back to top]
[Purchase Article] [PMID: 19149611 PubMed - indexed for MEDLINE]
Nuclear Medicine: Proof of Principle for Targeted
Drugs in Diagnosis and Therapy
T. Leitha
Delivering a drug to a specific target in the body is comparable
to the "magic bullet principle" applied in Nuclear
Medicine. If clinical medicine today found treatment options
by targeting specific receptors, proteins or enzymes by "small-molecule
drugs" it utilizes concepts that have been initially
described by Nobel Laureate George von Hevesy as “tracer
principle”.
This article is going to show that molecular imaging probes
in Nuclear Medicine can be regarded as proof of principle
of many of recent trends in diagnosis and therapy and offers
exciting opportunities for further developments.
Radioiodine therapy of benign and malignant thyroid disease
has been established in Nuclear Medicine over six decades
ago and is a fine example for using the same highly specific
probe for diagnosis and treatment of a given disease. The
use of radio labeled monoclonal antibodies against surface
receptors of tumor cells (e.g. CEA) dominated diagnostic Nuclear
Medicine in the eighties and sees a recent revival in lymphoma
treatment radioimmunotherapy.
Finally Nuclear Medicine has shown that it may advance drug
development by visualizing its biodistribution and site of
action. On the other hand some drugs like somatostatin analogues
have been reinvented as diagnostic and therapeutic probes
over a decade after their initial introduction as therapeutics.
Molecular Imaging and targeted therapy are merging and potentate
their individual strength. Nuclear Medicine has ample experience
in applying Molecular Imaging in clinical research and practice
and has a bright future in this exciting field.
[Back to top]
[Purchase Article] [PMID: 19149612 PubMed - indexed for MEDLINE]
Targeted Therapies in Lung Cancer
R. Pirker and M. Filipits
Targeted therapies have improved and will continue to improve
the outcome of lung cancer. Current strategies focus on the
blockade of growth factor receptors and the inhibition of
angiogenesis. Epidermal growth factor receptor (EGFR)-directed
tyrosine kinase inhibitors (TKIs) have already been established
as a treatment option in patients with advanced non-small
cell lung cancer (NSCLC) progressing after prior treatment
with chemotherapy. EGFR-directed monoclonal antibodies in
combination with platinum-based first-line chemotherapy have
shown promising efficacy in phase II trials. In a phase III
trial, cetuximab combined with cisplatin/vinorelbine resulted
in superior survival compared to chemotherapy alone in patients
with advanced EGFR-positive NSCLC. Inhibition of angiogenesis
has also been successfully applied as a new treatment strategy.
Bevacizumab added to palliative chemotherapy has improved
progression-free survival in two phase III trials and overall
survival in one of these trials in selected patients with
advanced non-squamous cell lung cancer. Bevacizumab is now
approved for selected patients with advanced NSCLC in combination
with platinum-based chemotherapy. Other targeted therapies
including dual and multi-kinase inhibitors are in earlier
stages of clinical development. In small cell lung cancer
(SCLC), targeted therapies have also been studied but no clinical
benefit could be demonstrated for these agents.
[Back to top]
[Purchase Article] [PMID: 19149613 PubMed - indexed for MEDLINE]
Targeted Therapies in Solid Tumours: Pinpointing the
Tumour’s Achilles Heel
G. Kornek and E. Selzer
It is now exactly 100 years ago (1908) that Paul Ehrlich,
who is regarded as the inventor of the concept of targeted
therapy, received the Nobel Prize for Medicine. His initial
perception leading to this theory was derived from observations
that certain substances are capable of selectively staining
either tissues or microorganisms. These observations culminated
in the discovery of the inorganic mercury compound arsphenamine
(Salvarsan®) by Sahachiro
Hata in the laboratory of Paul Ehrlich. Salvarsan®
might be regarded as the first effective “targeted”
treatment for syphilis at that time. Tamoxifen (Nolvadex®),
an anti-estrogen, which was introduced in the early 1970s,
was one of the first rationally designed targeted anti-tumour
drugs. Since the 1970s a dramatic development of new molecular
technologies occurred, culminating, for example, into the
Human Genome Project and the public availability of various
gene and protein databases, such as the Cancer Genome Anatomy
Program established by the National Cancer Institute. Genomics,
proteomics, structural genomics, transcriptomics, and high-throughput
screening technologies for identification of targeted drugs
are now available, which were almost unimaginable only a few
years ago. Over 500 kinases are known of which about 250 have
been cloned and are available to directly evaluate the activity
of novel drug candidates. These technologies in conjunction
with bio-informatic and chemical tools allow us to design
novel molecules, and consequently tailor drug therapy to specific
targets within tumours.
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