Pharmacological Reviews,
Год журнала:
2025,
Номер
77(3), С. 100042 - 100042
Опубликована: Янв. 22, 2025
Cyclic
nucleotides
are
synthesized
by
adenylyl
and/or
guanylyl
cyclase,
and
downstream
of
this
synthesis,
the
cyclic
nucleotide
phosphodiesterase
families
(PDEs)
specifically
hydrolyze
nucleotides.
PDEs
control
adenosine-3',5'monophosphate
(cAMP)
guanosine-3',5'-monophosphate
(cGMP)
intracellular
levels
mediating
their
quick
return
to
basal
steady
state
levels.
This
often
takes
place
in
subcellular
nanodomains.
Thus,
govern
short-term
protein
phosphorylation,
long-term
expression,
even
epigenetic
mechanisms
modulating
Consequently,
involvement
both
health
disease
is
extensively
investigated.
PDE
inhibition
has
emerged
as
a
promising
clinical
intervention
method,
with
ongoing
developments
aiming
enhance
its
efficacy
applicability.
In
comprehensive
review,
we
look
into
intricate
landscape
biochemistry,
exploring
diverse
roles
various
tissues.
Furthermore,
outline
underlying
different
pathophysiological
conditions.
Additionally,
review
application
related
diseases,
shedding
light
on
current
advancements
future
prospects
for
intervention.
SIGNIFICANCE
STATEMENT:
Regulating
critical
checkpoint
numerous
(patho)physiological
However,
despite
development
several
inhibitors
aimed
at
controlling
overactivated
PDEs,
applicability
settings
poses
challenges.
context,
our
focus
pharmacodynamics
structure
activity
illustrate
how
selectivity
can
be
optimized.
points
preclinical
evidence
that
depicts
optimization
efforts
indications.
Journal of the American Chemical Society,
Год журнала:
2023,
Номер
145(30), С. 16642 - 16649
Опубликована: Июль 21, 2023
Confining
the
protein
degradation
activity
of
proteolysis-targeting
chimera
(PROTAC)
to
cancer
lesions
ensures
precision
treatment.
However,
it
still
remains
challenging
precisely
control
PROTAC
function
in
tumor
regions
vivo.
We
herein
describe
a
near-infrared
(NIR)
photoactivatable
nano-PROTAC
(NAP)
for
remote-controllable
proteolysis
tumor-bearing
mice.
NAP
is
formed
by
molecular
self-assembly
from
an
amphiphilic
conjugate
linked
with
NIR
photosensitizer
through
singlet
oxygen
(1O2)-cleavable
linker.
The
initially
silenced
but
can
be
remotely
switched
on
upon
photoirradiation
generate
1O2
photosensitizer.
demonstrated
that
enabled
tumor-specific
bromodomain-containing
4
(BRD4)
light-instructed
manner.
This
combination
photodynamic
therapy
(PDT)
elicited
effective
suppression
growth.
work
thus
presents
novel
approach
spatiotemporal
over
targeted
PROTAC.
Abstract
Proteolysis-targeting
chimeras
(PROTACs)
technology
has
garnered
significant
attention
over
the
last
10
years,
representing
a
burgeoning
therapeutic
approach
with
potential
to
address
pathogenic
proteins
that
have
historically
posed
challenges
for
traditional
small-molecule
inhibitors.
PROTACs
exploit
endogenous
E3
ubiquitin
ligases
facilitate
degradation
of
interest
(POIs)
through
ubiquitin–proteasome
system
(UPS)
in
cyclic
catalytic
manner.
Despite
recent
endeavors
advance
utilization
clinical
settings,
majority
fail
progress
beyond
preclinical
phase
drug
development.
There
are
multiple
factors
impeding
market
entry
PROTACs,
insufficiently
precise
favorable
POIs
standing
out
as
one
most
formidable
obstacles.
Recently,
there
been
exploration
new-generation
advanced
including
PROTAC
prodrugs,
biomacromolecule-PROTAC
conjugates,
and
nano-PROTACs,
improve
vivo
efficacy
PROTACs.
These
improved
possess
capability
mitigate
undesirable
physicochemical
characteristics
inherent
thereby
enhancing
their
targetability
reducing
off-target
side
effects.
The
will
mark
pivotal
turning
point
realm
targeted
protein
degradation.
In
this
comprehensive
review,
we
meticulously
summarized
state-of-the-art
advancements
achieved
by
these
cutting-edge
elucidated
underlying
design
principles,
deliberated
upon
prevailing
encountered,
provided
an
insightful
outlook
on
future
prospects
within
field.
Advanced Materials,
Год журнала:
2024,
Номер
36(23)
Опубликована: Фев. 14, 2024
Abstract
Radiation
therapy
(RT)
is
one
of
the
primary
options
for
clinical
cancer
therapy,
in
particular
advanced
head
and
neck
squamous
cell
carcinoma
(HNSCC).
Herein,
crucial
role
bromodomain‐containing
protein
4
(BRD4)‐RAD51
associated
1
(RAD51AP1)
axis
sensitizing
RT
HNSCC
revealed.
A
versatile
nanosensitizer
(RPB7H)
thus
innovatively
engineered
by
integrating
a
PROteolysis
TArgeting
Chimeras
(PROTAC)
prodrug
(BPA771)
hafnium
dioxide
(HfO
2
)
nanoparticles
to
downregulate
BRD4‐RAD51AP1
pathway
sensitize
tumor
RT.
Upon
intravenous
administration,
RPB7H
selectively
accumulate
at
tissue
internalize
into
cells
recognizing
neuropilin‐1
overexpressed
mass.
HfO
enhance
effectiveness
amplifying
X‐ray
deposition,
intensifying
DNA
damage,
boosting
oxidative
stress.
Meanwhile,
BPA771
can
be
activated
RT‐induced
H
O
secretion
degrade
BRD4
inactivate
RAD51AP1,
impeding
damage
repair.
This
nanosensitizer,
combined
with
irradiation,
effectively
regresses
growth
mouse
model.
The
findings
introduce
PROTAC
prodrug‐based
radiosensitization
strategy
targeting
axis,
may
offer
promising
avenue
augment
more
effective
therapy.
Angewandte Chemie International Edition,
Год журнала:
2024,
Номер
63(18)
Опубликована: Фев. 19, 2024
The
cell
membrane
is
a
crucial
component
of
cells,
protecting
their
integrity
and
stability
while
facilitating
signal
transduction
information
exchange.
Therefore,
disrupting
its
structure
or
impairing
functions
can
potentially
cause
irreversible
damage.
Presently,
the
tumor
recognized
as
promising
therapeutic
target
for
various
treatment
methods.
Given
extensive
research
focused
on
membranes,
it
both
necessary
timely
to
discuss
these
developments,
from
materials
design
specific
biomedical
applications.
This
review
covers
treatments
based
functional
targeting
membrane,
ranging
well-known
membrane-anchoring
photodynamic
therapy
recent
lysosome-targeting
chimaeras
protein
degradation.
diverse
mechanisms
are
introduced
in
following
sections:
phototherapy,
self-assembly
situ
biosynthesis
degradation
proteins
by
chimeras.
In
each
section,
we
outline
conceptual
general
derived
numerous
studies,
emphasizing
representative
examples
understand
advancements
draw
inspiration.
Finally,
some
challenges
future
directions
membrane-targeted
our
perspective.
aims
engage
multidisciplinary
readers
encourage
researchers
related
fields
advance
fundamental
theories
practical
applications
membrane-targeting
agents.
Nanoscale,
Год журнала:
2024,
Номер
16(9), С. 4378 - 4391
Опубликована: Янв. 1, 2024
Schematic
illustration
of
the
combinational
strategy
nanotechnology
and
PROTACs
(Nano-PROTACs):
typical
shortcomings
traditional
nanotechnology-based
strategies
for
PROTAC
drugs
optimization.
