The poly (ADP-ribose) polymerase 1 (PARP1) enzyme is one of the promising molecular targets for the discovery of antitumor drugs. PARP1 is a common nuclear protein (1-2 million molecules per cell) serving as a “sensor” for DNA strand breaks. Increased PARP1 expression is sometimes observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. The PARP1 expression level is a prognostic indicator and is associated with a poor survival prognosis. There is evidence that high PARP1 expression and treatment-resistance of tumors are correlated. PARP1 inhibitors are promising antitumor agents, since they act as chemo- and radiosensitizers in the conventional …
Cell Reports,
Journal Year:
2018,
Volume and Issue:
23(1), P. 270 - 281.e3
Published: April 1, 2018
For
the
past
decade,
cancer
genomic
studies
have
focused
on
mutations
leading
to
splice-site
disruption,
overlooking
those
having
splice-creating
potential.
Here,
we
applied
a
bioinformatic
tool,
MiSplice,
for
large-scale
discovery
of
splice-site-creating
(SCMs)
across
8,656
TCGA
tumors.
We
report
1,964
originally
mis-annotated
clear
evidence
creating
alternative
splice
junctions.
TP53
and
GATA3
26
18
SCMs,
respectively,
ATRX
has
5
from
lower-grade
gliomas.
Mutations
in
11
genes,
including
PARP1,
BRCA1,
BAP1,
were
experimentally
validated
function.
Notably,
found
that
neoantigens
induced
by
SCMs
are
likely
several
folds
more
immunogenic
compared
missense
mutations,
exemplified
recurrent
SCM.
Further,
high
expression
PD-1
PD-L1
was
observed
tumors
with
suggesting
candidates
immune
blockade
therapy.
Our
work
highlights
importance
integrating
DNA
RNA
data
understanding
functional
clinical
implications
human
diseases.
ChemMedChem,
Journal Year:
2021,
Volume and Issue:
16(12), P. 1861 - 1877
Published: March 1, 2021
Benzimidazole
is
a
heterocyclic
ring
system
that
has
been
widely
studied
in
the
pharmaceutical
field.
For
past
decade,
numerous
benzimidazole
derivatives
have
synthesized
and
evaluated
for
their
wide
range
of
pharmacological
activities,
which
are
beneficial
drug
development.
This
article
presents
biological
effects
each
invention
from
2015
to
2020.
Two
patent
databases,
Google
Patents
Lens,
were
used
locate
relevant
granted
applications.
Specifically,
this
review
delineates
role
patented
benzimidazoles
disease-centric
perspective
examines
mechanisms
action
these
compounds
related
diseases.
Most
shown
good
activities
against
various
target
proteins.
Whilst
several
them
progressed
into
clinical
trials,
most
patents
presented
novel
therapeutic
approaches
respective
Hence,
potential
being
developed
drugs
also
discussed.
Chemical Biology & Drug Design,
Journal Year:
2023,
Volume and Issue:
102(2), P. 357 - 376
Published: April 3, 2023
Cancer
is
the
second
leading
cause
of
death
globally,
with
9.6
million
deaths
yearly.
As
a
life-threatening
disease,
it
necessitates
emergence
new
therapies.
Resistance
to
current
chemotherapies
drives
scientists
develop
medications
that
will
eventually
be
accessible.
Because
heterocycles
are
so
common
in
biological
substances,
compounds
play
big
part
variety
have
been
developed.
The
"Master
Key"
benzimidazole
nucleus,
which
consists
six-membered
benzene
ring
fused
five-membered
imidazole/imidazoline
ring,
an
azapyrrole.
One
aromatic
nitrogen
identified
American
therapies
approved
by
Food
and
Drug
Administration
(FDA).
Our
results
show
benzimidazole's
broad
therapeutic
spectrum
due
its
structural
isosteres
purine,
improves
hydrogen
bonding,
electrostatic
interactions
topoisomerase
complexes,
intercalation
DNA,
other
functions.
It
also
enhances
protein
nucleic
acid
inhibition,
tubulin
microtubule
degeneration,
apoptosis,
DNA
fragmentation,
Additionally,
readers
for
designing
more
recent
analogues
as
prospective
cancer
treatments.
Cell Communication and Signaling,
Journal Year:
2017,
Volume and Issue:
15(1)
Published: Oct. 10, 2017
Fanconi
Anemia
(FA)
is
a
rare,
inherited
genomic
instability
disorder,
caused
by
mutations
in
genes
involved
the
repair
of
interstrand
DNA
crosslinks
(ICLs).
The
FA
signaling
network
contains
unique
nuclear
protein
complex
that
mediates
monoubiquitylation
FANCD2
and
FANCI
heterodimer,
coordinates
activities
downstream
pathway
including
nucleotide
excision
repair,
translesion
synthesis,
homologous
recombination.
proteins
act
at
different
steps
ICL
sensing,
recognition
processing
lesions.
multi-protein
tightly
regulated
mechanisms,
such
as
ubiquitination,
phosphorylation,
degradation
signals
are
critical
for
maintenance
genome
integrity
suppressing
tumorigenesis.
Here,
we
discuss
recent
advances
our
understanding
how
participate
regulation
assures
safeguard
genome.
We
further
potential
application
designing
small
molecule
inhibitors
inhibit
synthetic
lethal
with
enzymes
can
be
used
cancer
therapeutics.
International Journal of Molecular Sciences,
Journal Year:
2017,
Volume and Issue:
18(10), P. 2111 - 2111
Published: Oct. 8, 2017
Poly
(ADP-ribose)
polymerase
1
(PARP1),
the
best-studied
isoform
of
nuclear
enzyme
PARP
family,
plays
a
pivotal
role
in
cellular
biological
processes,
such
as
DNA
repair,
gene
transcription,
and
so
on.
PARP1
has
been
found
to
be
overexpressed
various
carcinomas.
These
all
indicate
clinical
potential
therapeutic
target
human
malignancies.
Additionally,
multiple
preclinical
research
studies
trials
demonstrate
that
inhibition
can
repress
tumor
growth
metastasis.
Up
until
now,
inhibitors
are
clinically
used
not
only
for
monotherapy
suppress
tumors,
but
also
adjuvant
therapy,
maintain
or
enhance
effects
mature
antineoplastic
drugs,
well
protect
patients
from
chemotherapy
surgery-induced
injury.
To
supply
framework
understanding
recent
progress
carcinomas,
we
review
structure,
expression,
functions,
mechanisms
PARP1,
summarize
PARP1-related
anticancer
agents,
provide
some
ideas
development
other
promising
therapy.
Journal of Medicinal Chemistry,
Journal Year:
2019,
Volume and Issue:
62(6), P. 3051 - 3067
Published: March 7, 2019
Poly(ADP-ribose)
polymerase-1
(PARP-1)
is
a
new
potential
target
for
anticancer
drug
discovery.
A
series
of
bromophenol–thiosemicarbazone
hybrids
as
PARP-1
inhibitors
were
designed,
synthesized,
and
evaluated
their
antitumor
activities.
Among
them,
the
most
promising
compound,
11,
showed
excellent
selective
inhibitory
activity
(IC50
=
29.5
nM)
over
PARP-2
>
1000
potent
activities
toward
SK-OV-3,
Bel-7402
HepG2
cancer
cell
lines
2.39,
5.45,
4.60
μM),
along
with
inhibition
tumor
growth
in
an
vivo
SK-OV-3
xenograft
model.
Further
study
demonstrated
that
compound
11
played
role
through
multiple
mechanisms,
including
induction
apoptosis
cycle
arrest,
cellular
accumulation
DNA
double-strand
breaks,
repair
alterations,
H2O2-triggered
PARylation,
antiproliferative
effects
via
production
cytotoxic
reactive
oxygen
species,
autophagy.
In
addition,
displayed
good
pharmacokinetic
characteristics
favorable
safety.
These
observations
demonstrate
may
serve
lead
discovery
drugs.
