Angewandte Chemie International Edition,
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 9, 2024
Abstract
Proteolysis‐targeting
chimeras
(PROTACs)
have
accelerated
drug
development;
however,
some
challenges
still
exist
owing
to
their
lack
of
tumor
selectivity
and
on‐demand
protein
degradation.
Here,
we
developed
a
miR
NA‐
i
nitiated
ssembled
pre‐PRO
TAC
(miRiaTAC)
platform
that
enables
the
activation
termination
target
degradation
in
cell
type‐specific
manner.
Using
miRNA‐21
as
model,
engineered
DNA
hairpins
labeled
with
JQ‐1
pomalidomide
facilitated
modular
assembly
DNA‐encoded
pre‐PROTACs
through
hybridization
chain
reaction.
This
configuration
promoted
selective
polyubiquitination
BRD4
upon
miR‐21
initiation,
highlighting
significant
minimal
systemic
toxicity.
Furthermore,
incorporates
photolabile
groups,
enabling
precise
optical
control
during
assembly/disassembly,
mitigating
risk
excessive
Additionally,
by
introducing
secondary
ligand
targeting
CDK6,
these
were
used
scaffold
for
programmable
active
miRiaTACs
containing
two
different
warheads
exact
stoichiometry,
orthogonal
multitarget
The
integration
near‐infrared
light‐mediated
photodynamic
therapy
an
upconversion
nanosystem
further
enhanced
efficacy
potent
vivo
anticancer
activity.
We
anticipate
miRiaTAC
represents
intersection
between
dynamic
nanotechnology
PROTAC,
potentially
expanding
versatility
PROTAC
toolkit
cancer
therapy.
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.
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.
Journal of the American Chemical Society,
Год журнала:
2023,
Номер
145(40), С. 21860 - 21870
Опубликована: Сен. 14, 2023
Proteolysis
Targeting
Chimera
(PROTAC)
technology
represents
a
promising
new
approach
for
target
protein
degradation
using
cellular
ubiquitin-proteasome
system.
Recently,
we
developed
split-and-mix
nanoplatform
based
on
peptide
self-assembly,
which
could
serve
as
self-adjustable
platform
multifunctional
applications.
However,
the
lower
drug
efficacy
limits
further
biomedical
applications
of
peptide-based
SM-PROTAC.
In
this
study,
develop
novel
PROTAC
system
liposome
self-assembly
(LipoSM-PROTAC),
concurrent
with
modification
FA
(folate)
to
enhance
its
tumor-targeting
capabilities.
Estrogen
receptors
(ERα)
were
chosen
interest
(POI)
validate
Lipo
degraders.
Results
demonstrate
that
can
be
efficiently
and
selectively
taken
up
into
cells
by
receptor-positive
(FR+)
degrade
POI
significantly
reduced
concentration.
Compared
SM-PROTACs,
our
designed
LipoSM-PROTAC
achieve
therapeutic
concentration
provide
opportunities
clinical
translational
potential.
Overall,
LipoSM-based
shows
higher
efficacy,
offers
potential
other
biomolecule
regulations.
Advanced Materials,
Год журнала:
2024,
Номер
36(38)
Опубликована: Июнь 20, 2024
Abstract
While
proteolysis‐targeting
chimeras
(PROTACs)
hold
great
potential
for
persistently
reprogramming
the
immunosuppressive
tumor
microenvironment
via
targeted
protein
degradation,
precisely
activating
them
in
tissues
and
preventing
uncontrolled
proteolysis
at
off‐target
sites
remain
challenging.
Herein,
a
light‐triggered
PROTAC
nanoassembly
(LPN)
photodynamic
indoleamine
2,3‐dioxygenase
(IDO)
is
reported.
The
LPN
derived
from
self‐assembly
of
prodrug
conjugates,
which
comprise
PROTAC,
cathepsin
B‐specific
cleavable
peptide
linker,
photosensitizer,
without
any
additional
carrier
materials.
In
colon
models,
intravenously
injected
LPNs
initially
silence
activity
PROTACs
accumulate
significantly
due
to
an
enhanced
permeability
retention
effect.
Subsequently,
cancer
biomarker
B
begins
trigger
release
active
through
enzymatic
cleavage
linkers.
Upon
light
irradiation,
cells
undergo
immunogenic
cell
death
induced
by
therapy
promote
activation
effector
T
cells,
while
continuous
IDO
degradation
simultaneously
blocks
tryptophan
metabolite‐regulated
regulatory‐T‐cell‐mediated
immunosuppression.
Such
LPN‐mediated
combinatorial
effectively
inhibits
growth,
metastasis,
recurrence.
Collectively,
this
study
presents
promising
nanomedicine,
designed
synergize
with
other
immunotherapeutic
modalities,
more
effective
safer
immunotherapy.
Advanced Materials,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 3, 2025
Abstract
Glioblastoma
(GBM)
is
the
most
aggressive
subtype
of
primary
brain
tumors,
which
marginally
respond
to
standard
chemotherapy
due
blood‐brain
barrier
(BBB)
and
low
tumor
specificity
therapeutics.
Herein,
a
double‐layered
microneedle
(MN)
patch
rationally
engineered
by
integrating
acid
light
dual‐activatable
PROteolysis
TArgeting
Chimera
(PROTAC)
nanoparticles
self‐oxygenating
BSA‐MnO
2
(BM)
for
GBM
treatment.
The
MN
administrated
at
site
locally
deliver
PROTAC
prodrug
BM
nanoparticles.
are
rapidly
released
from
outer
layer
specifically
activated
in
acidic
intracellular
environment
cells.
Subsequently,
near‐infrared
activates
photosensitizer
produce
singlet
oxygen
(
1
O
)
through
photodynamic
therapy
(PDT),
thereby
triggering
spatiotemporally‐tunable
degradation
bromodomain
extraterminal
protein
4
(BRD4).
nanoparticles,
inner
MN,
serve
as
an
supply
station,
counteracts
hypoxia
converting
hydrogen
peroxide
(H
into
(O
),
thus
promoting
PDT
activation.
This
prodrug‐integrated
significantly
inhibits
growth
both
subcutaneous
orthotopic
models.
study
describes
first
strategy
highly
efficient
therapy,
potentially
advancing
precise
other
kinds
refractory
tumors.
The
development
of
miniaturized
high-throughput
in
situ
screening
platforms
capable
handling
the
entire
process
drug
synthesis
to
final
is
essential
for
advancing
discovery
future.
In
this
study,
an
approach
based
on
combinatorial
solid-phase
synthesis,
enabling
efficient
libraries
proteolysis
targeting
chimeras
(PROTACs)
array
format
presented.
This
on-chip
platform
allows
direct
biological
without
need
transfer
steps.
UV-induced
release
target
molecules
into
individual
droplets
facilitates
further
experimentation.
Utilizing
a
mitogen-activated
protein
kinase
kinases
(MEK1/2)
degrader
as
template,
series
132
novel
PROTAC-like
synthesized
using
Ugi
reaction.
These
compounds
are
characterized
various
methods,
including
matrix-assisted
laser
desorption
ionization
mass
spectrometry
(MALDI-MS)
imaging,
while
consuming
only
few
milligrams
starting
materials
total.
Furthermore,
feasibility
culturing
cancer
cells
modified
spots
and
quantifying
effect
MEK
suppression
demonstrated.
lays
foundation
potent
PROTACs
potential
anticancer
activity
offers
accelerating
by
integrating
steps
same
array.
Biomaterials Research,
Год журнала:
2024,
Номер
2024
Опубликована: Июль 10, 2024
Triple-negative
breast
cancer
(TNBC)
is
a
special
subtype
of
cancer,
which
highly
aggressive
and
incurable.
Here,
we
proposed
an
ultrasound
activatable
bromodomain-containing
protein
4
(BRD4)
proteolysis
targeting
chimera
(PROTAC)
release
strategy
for
the
first
time
precisely
controlled
degradation
in
preclinical
TNBC
model.
Through
combination
PROTAC
ultrasound-targeted
microbubble
destruction
(UTMD)
technology,
present
also
aims
to
concurrently
solve
major
limitations
poor
loading
capacity
microbubbles
undesirable
membrane
permeability
PROTAC.
(ARV-825)-encapsulated
microbubbles,
ARV-MBs,
were
developed
efficacious
treatment
vitro
vivo.
The
synthesized
showed
ultrasound-responsive
drug
ability,
could
effectively
promote
penetration
into
tumor
site
cell.
Under
ultrasound,
ARV-MBs
play
effective
antitumor
effect
by
potentiating
ubiquitination
BRD4
tumor.
current
study
may
provide
new
idea
promoting
clinical
translation
drug-loaded
PROTAC,
offer
therapeutic
modality
TNBC.