| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 17, Number 13, 2010
Contents
New Opportunities to Treat the T315I-Bcr-Abl Mutant in Chronic
Myeloid Leukaemia: Tyrosine Kinase Inhibitors and Molecules
that Act by Alternative Mechanisms Pp. 1220-1245
S. Schenone, C. Brullo and M. Botta
[Abstract] [Purchase
Article]
[PMID: 20166937 PubMed - indexed for MEDLINE]
Reversing Aberrant
Methylation Patterns in Cancer Pp. 1246-1254
F.S. Poke, A. Qadi and A.F. Holloway
[Abstract] [Purchase
Article] [PMID:
20166939 PubMed - indexed for MEDLINE]
Editor’s
Choice
Targeting αvβ3
Integrin: Design and Applications of Mono- and Multifunctional
RGD-Based Peptides and Semipeptides Pp.
1255-1299
L. Auzzas, F. Zanardi, L. Battistini, P. Burreddu, P. Carta,
G. Rassu, C. Curti and G. Casiraghi
[Abstract] [Purchase
Article] [PMID:
20166941 PubMed - indexed for MEDLINE]
Primate-Accelerated Evolutionary Genes: Novel Routes
to Drug Discovery in Psychiatric Disorders Pp. 1300-1316
J.-M. Moalic, Y. Le Strat, A.-M. Lepagnol-Bestel, N. Ramoz,
Y. Loe-Mie, G. Maussion, P. Gorwood and M. Simonneau
[Abstract] [Purchase
Article]
[PMID:
20166940 PubMed - indexed for MEDLINE]
Role of COL4A1 in Basement-Membrane Integrity and
Cerebral Small-Vessel Disease. The COL4A1 Stroke
Syndrome Pp. 1317-1324
I. Volonghi, A. Pezzini, E. Del Zotto, A. Giossi, P. Costa,
D. Ferrari and A. Padovani
[Abstract] [Purchase
Article]
[PMID:
20166936 PubMed - indexed for MEDLINE]
Coumarins: Old Compounds with Novel Promising Therapeutic
Perspectives Pp. 1325-1338
M.E. Riveiro, N. De Kimpe, A. Moglioni, R. Vázquez,
F. Monczor, C. Shayo and C. Davio
[Abstract] [Purchase
Article]
[PMID:
20166938 PubMed - indexed for MEDLINE]
Abstracts
[Back to top] [Purchase
Article] [PMID:
20166937 PubMed - indexed for MEDLINE]
New Opportunities to Treat the T315I-Bcr-Abl Mutant in Chronic
Myeloid Leukaemia: Tyrosine Kinase Inhibitors and Molecules
that Act by Alternative Mechanisms
S. Schenone, C. Brullo and M. Botta
Resistance to the Bcr-Abl inhibitors approved for the treatment
of chronic myeloid leukaemia (CML) may arise from different
mechanisms, including Bcr-Abl amino acid mutations, gene amplification
and mechanisms independent of Bcr-Abl. The T315I mutation
at the gatekeeper residue is very frequent in advanced phases
of the disease and is one of the main causes of resistance,
disrupting important contact points between the inhibitors
and the enzyme.
Different strategies have been implemented to overcome this
resistance, including the synthesis of new Bcr-Abl ATP-competitive
or non-ATP-competitive inhibitors, dual Aurora/Bcr-Abl inhibitors
and multi-targeted kinase inhibitors. An alternative approach
is the use of other compounds that do not bind directly to
the Bcr-Abl protein; instead, these molecules act on several
downstream pathways, regulated by or linked in different ways
to Bcr-Abl, that lead to the malignant transformation of the
cells.
For this reason, farnesyl transferase inhibitors, MAPK inhibitors,
Rac guanosine triphosphatase inhibitors, PI3K inhibitors,
JAK inhibitors, Hsp90 inhibitors, mTOR inhibitors, PP2A activators
and apoptosis inducers have been tested, alone or in combination
with ATP-competitive inhibitors, against CML cell lines.
This review discusses compounds that act on Bcr-Abl or different
cell pathways and reports on the molecules active against
the T315I mutation, particularly the most recent findings
in this field. New molecules that are claimed by recent patents
to be active on this mutation are also reported.
When possible, the review will focus on medicinal chemistry
in terms of chemical structure, mechanism of action and structure-activity
relationships.
[Back to top] [Purchase
Article] [PMID:
20166939 PubMed - indexed for MEDLINE]
Reversing Aberrant
Methylation Patterns in Cancer
F.S. Poke, A. Qadi and A.F. Holloway
Changes to the epigenetic information within a cell play a
significant role in cancer development and progression. These
epigenetic changes are important in establishing the aberrant
gene expression patterns that are a feature of cancer cell
biology. We are currently experiencing a rapid advance in
our understanding of how epigenetic information is written
and interpreted in the cell, and the enzymes involved in these
processes have been recognised as prime targets for therapeutic
intervention. Reagents that target these enzymes have the
potential to inhibit or reverse epigenetic changes in cancer
cells. Evidence suggests that the aberrant regulation of two
gene silencing pathways; involving DNA methylation and histone
methylation, play an important role in cancer development.
Considerable effort is being exerted in the development of
inhibitors of these pathways. However, complex functional
interactions exist between the DNA and histone methylation
pathways, and these interactions will need to be considered
in the design of inhibitory molecules. This review details
current research into agents developed as inhibitors of these
epigenetic pathways, focusing on the types of epigenetic modifications
being targeted, interactions between these modifications and
the use of these inhibitory agents in cancer treatment.
[Back to top] [Purchase
Article] [PMID:
20166941 PubMed - indexed for MEDLINE]
Targeting αvβ3
Integrin: Design and Applications of Mono- and Multifunctional
RGD-Based Peptides and Semipeptides
L. Auzzas, F. Zanardi, L. Battistini, P. Burreddu, P. Carta,
G. Rassu, C. Curti and G. Casiraghi
The outstanding physio-pathological role played by integrin
receptors in living subjects motivates the enormous interest
shown by scientists worldwide for this topic. More than twenty
years of research has spanned across the structural and functional
elucidation of these proteins and over their antagonism-based
biomedical applications. The proof-of-concept stage, aimed
at identifying potent inhibitors, covered a decade of studies,
and paved the way for a more advanced era of research where
these antagonist molecules were thrown into the deep end of
applicative studies. This review intends to summarize the
major efforts conducted thus far and focuses on the design,
synthesis and biomedical applications of cyclic RGD-containing
αvβ3
integrin antagonists, in both their small and macromolecular
formats. In particular, Chapters 1 and 2 offer a comprehensive
outlook on the rational basis for the design of integrin inhibitors,
Chapter 3 chronicles the biological and medical applications
of monofunctional RGD integrin ligands both in their monomeric
and multimeric asset, and Chapter 4 illustrates the potential
of RGD-based multifunctional systems in molecular medicine.
[Back to top] [Purchase
Article] [PMID:
20166940 PubMed - indexed for MEDLINE]
Primate-Accelerated Evolutionary Genes: Novel Routes
to Drug Discovery in Psychiatric Disorders
J.-M. Moalic, Y. Le Strat, A.-M. Lepagnol-Bestel, N. Ramoz,
Y. Loe-Mie, G. Maussion, P. Gorwood and M. Simonneau
Novel molecular genetic approaches, at genome-scale in different
species allowed characterizing genes that have undergone recent
selection. The interest in this research field is not limited
to the natural curiosity about our evolutionary past, but
it is also to identify novel susceptibility genes for neuropsychiatic
disorders by pointing specific human traits, such as behavioral
and cognitive abilities. Hypotheses have been proposed to
relate specific psychiatric disorders to the origin of modern
humans, as evidenced by the theory of Crow about schizophrenia.
In the present review, we will focus on genes that underwent
positive selection in humans or displayed a human specific
evolutionary pattern and which were reported as associated
with psychiatric disorders. This will include the (1) DRD4
gene associated with attention-deficit/hyperactivity disorder,
located in a locus that underwent a positive selection; the
(2) GABRB2 gene, a gene associated with schizophrenia
and recently reported as the target of a positive selection;
(3) MARK1, a candidate gene for autism that was reported
as displaying a signature of adaptative evolution in the human
lineage, and (4) the ADH and ALDH2 genes
which are associated with alcoholism, and for which evidence
of positive selection was identified in the human lineage
since the divergence between humans and chimpanzees. Identification
of novel candidate genes based on recent evolution selection,
coupled to genome-wide strategies designed to detect rare
structural variants, could lead to a better knowledge of the
molecular mechanisms of neurodevelopmental disorders and might
therefore help to develop new medical chemistry.
[Back to top] [Purchase
Article]
[PMID: 20166936 PubMed - indexed for MEDLINE]
Role of COL4A1 in Basement-Membrane Integrity and
Cerebral Small-Vessel Disease. The COL4A1 Stroke
Syndrome
I. Volonghi, A. Pezzini, E. Del Zotto, A. Giossi, P. Costa,
D. Ferrari and A. Padovani
Type IV collagens are basement membrane (BM) proteins expressed
in all tissues including the vasculature. COL4A1 and COL4A2,
the most abundant type IV collagens, form heterotrimers with
a 2:1 stoichiometry and each heterotrimer forms a triple helix
along the length of the collagenous domains. Recently, mutations
in COL4A1 on chromosome 13q34, encoding the a1 chain of type
IV collagen, have been linked to a spectrum of cerebral small-vessel
disease in humans, including perinatal intracerebral hemorrhage
(ICH) with consequent porencephaly, adult-onset ICH, microbleeds,
lacunar strokes, and leukoaraiosis, which follows an autosomal
dominant pattern of inheritance. This variable phenotype has
been named the “COL4A1 stroke syndrome”.
In COL4A1 stroke syndrome most mutations are missense mutations
involving a glycine residue, including G562E, G749S, G805R,
G1130D, G1236R, G1423R, G720D, G1580R, and G755R. Mutations
replacing a highly conserved hydrophobic glycine residue likely
lead to synthesis of an abnormal protein with abnormal structure
and inhibit heterotrimer secretion into the vascular BM, modify
its structural properties (when imaged with electron microscopy
BM is uneven, with inconsistent density and focal disruptions),
and, thus, increase the fragility of the vessel wall when
exposed to environmental factors. Although pathological changes
in BM also occur in other tissues (mostly retina and kidney),
the major site of vessel damage is the brain.
In the present review article we will focus on the molecular
basis of the COL4A1 stroke syndrome, summarize data on its
variable phenotype, and explore additional questions concerning
the possible genotype-phenotype correlations and the mechanisms
leading to cerebral small-vessel disease in this clinically
heterogeneous condition.
[Back to top] [Purchase
Article] [PMID:
20166938 PubMed - indexed for MEDLINE]
Coumarins: Old Compounds with Novel Promising Therapeutic
Perspectives
M.E. Riveiro, N. De Kimpe, A. Moglioni, R. Vázquez,
F. Monczor, C. Shayo and C. Davio
Natural as well as synthetic coumarins have recently
drawn much attention due to its broad pharmacological activities.
Many coumarins and their derivatives exert anti-coagulant,
anti-tumor, anti-viral, anti-inflammatory and anti-oxidant
effects, as well as anti-microbial and enzyme inhibition properties.
The recognition of key structural features within coumarin
family is crucial for the design and development of new analogues
with improved activity and for the characterization of their
mechanism of action and potential side effects. The different
substituents in the coumarin nucleus strongly influence the
biological activity of the resulting derivatives. Although
some coumarins have been already characterized to evoke a
particular biological activity, the challenge would be the
design and synthesis of new derivatives with high specific
activity for other pharmacological targets and define their
mechanism of action to achieve new therapeutic drugs. The
present review highligts the current progress in the development
of coumarin scaffolds for drug discovery as novel anti-cancer
agents. The major challenges about coumarins include the translation
of current knowledge into new potential lead compounds and
the repositioning of known compounds for the treatment of
cancer.
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