ChemBioChem,
Journal Year:
2024,
Volume and Issue:
26(1)
Published: Oct. 5, 2024
Abstract
Proteolysis‐targeting
chimera
(PROTAC)
has
emerged
as
an
attractive
therapeutic
modality
in
drug
discovery.
PROTACs
are
bifunctional
molecules
that
effectively
bridge
proteins
of
interest
(POIs)
with
E3
ubiquitin
ligases,
such
that,
the
target
tagged
and
subsequently
degraded
via
proteasome.
Despite
significant
progress
field
targeted
protein
degradation
(TPD),
application
conventional
PROTAC
degraders
still
faces
challenges,
including
systemic
toxicity
induced
by
non‐tissue‐specific
targeting.
To
address
this
issue,
a
variety
smart
can
be
activated
specific
stimuli,
have
been
developed
for
achieving
conditional
spatiotemporal
modulation
levels.
Here,
on
basis
our
contributions,
we
overview
recent
advances
PROTACs,
tumor
microenvironment‐,
photo‐,
X‐ray
radiation‐responsive
enable
controllable
TPD.
The
design
strategy,
case
studies,
potential
applications
challenges
will
focused
on.
Bioanalysis,
Journal Year:
2025,
Volume and Issue:
unknown, P. 1 - 16
Published: Feb. 3, 2025
Undruggable
targets
account
for
roughly
85%
of
human
disease-related
and
represent
a
category
therapeutic
that
are
difficult
to
tackle
with
traditional
methods,
but
their
considerable
clinical
importance.
These
generally
defined
by
planar
functional
interfaces
the
absence
efficient
ligand-binding
pockets,
making
them
unattainable
conventional
pharmaceutical
strategies.
The
advent
oligonucleotide-based
proteolysis-targeting
chimeras
(PROTACs)
has
instilled
renewed
optimism
in
addressing
these
challenges.
PROTACs
facilitate
targeted
degradation
undruggable
entities,
including
transcription
factors
(TFs)
RNA-binding
proteins
(RBPs),
via
proteasome-dependent
mechanisms,
thereby
presenting
novel
approaches
diseases
linked
targets.
This
review
offers
an
in-depth
examination
recent
progress
integration
PROTAC
technology
oligonucleotides
target
traditionally
proteins,
emphasizing
design
principles
mechanisms
action
innovative
PROTACs.
Bioconjugate Chemistry,
Journal Year:
2024,
Volume and Issue:
35(8), P. 1089 - 1115
Published: July 11, 2024
Targeted
protein
degradation
or
TPD,
is
rapidly
emerging
as
a
treatment
that
utilizes
small
molecules
to
degrade
proteins
cause
diseases.
TPD
allows
for
the
selective
removal
of
disease-causing
proteins,
including
proteasome-mediated
degradation,
lysosome-mediated
and
autophagy-mediated
degradation.
This
approach
has
shown
great
promise
in
preclinical
studies
now
being
translated
treat
numerous
diseases,
neurodegenerative
infectious
cancer.
review
discusses
latest
advances
its
potential
new
chemical
modality
immunotherapy,
with
special
focus
on
innovative
applications
cutting-edge
research
PROTACs
(Proteolysis
TArgeting
Chimeras)
their
efficient
translation
from
scientific
discovery
technological
achievements.
Our
also
addresses
significant
obstacles
prospects
this
domain,
while
offering
insights
into
future
immunotherapeutic
applications.
Chemical Biology & Drug Design,
Journal Year:
2024,
Volume and Issue:
104(5)
Published: Nov. 1, 2024
Cereblon
(CRBN),
a
member
of
the
E3
ubiquitin
ligase
complex,
has
gained
significant
attention
as
therapeutic
target
in
cancer.
CRBN
regulates
degradation
various
proteins
cancer
progression,
including
transcription
factors
and
signaling
molecules.
PROTACs
(proteolysis-targeting
chimeras)
are
novel
approach
that
uses
cell's
system
to
remove
disease-causing
selectively.
CRBN-dependent
work
by
tagging
harmful
for
destruction
through
ubiquitin-proteasome
system.
This
strategy
offers
several
advantages
over
traditional
protein
inhibition
methods,
potential
overcome
drug
resistance.
Recent
progress
developing
CRBN-based
shown
promising
preclinical
results
both
hematologic
malignancies
solid
tumors.
Additionally,
have
enhanced
our
understanding
CRBN's
role
cancer,
potentially
serving
biomarkers
patient
stratification
predicting
responses.
In
this
review,
we
delineate
mechanisms
action
(CRBN-PROTACs),
summarize
recent
advances
clinical
applications,
provide
perspective
on
future
development.
Journal of the American Chemical Society,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 3, 2025
Proteolysis-targeting
chimeras
(PROTACs)
are
dual-functional
molecules
composed
of
a
protein
interest
(POI)
ligand
and
an
E3
ligase
connected
by
linker,
which
can
recruit
POI
ligases
simultaneously,
thereby
inducing
the
degradation
showing
great
potential
in
disease
treatment.
A
challenge
developing
PROTACs
is
design
linkers
modification
ligands
to
establish
multifunctional
platform
that
enhances
efficiency
antitumor
activity.
As
programmable
modifiable
nanomaterial,
DNA
tetrahedron
precisely
assemble
selectively
recognize
flexibly
adjust
distance
between
molecules,
making
them
ideal
linkers.
Herein,
we
developed
multivalent
PROTAC
based
on
tetrahedron,
named
AS-TD2-PRO.
Using
as
combined
modules
targeting
tumor
cells,
recognizing
ligases,
multiple
together.
We
took
undruggable
target
signal
transducer
activator
transcription
3
(STAT3),
associated
with
etiology
progression
variety
malignant
tumors,
example
this
study.
AS-TD2-PRO
two
STAT3
recognition
demonstrated
good
enhancing
tumor-specific
compared
traditional
bivalent
PROTACs.
Furthermore,
mouse
model,
superior
therapeutic
activity
was
observed.
Overall,
tetrahedron-driven
both
serve
proof
principle
for
introduce
promising
avenue
cancer
treatment
strategies.
Pharmaceuticals,
Journal Year:
2025,
Volume and Issue:
18(3), P. 297 - 297
Published: Feb. 21, 2025
Absorption
and
permeability
are
critical
physicochemical
parameters
that
must
be
balanced
to
achieve
optimal
drug
uptake.
These
key
factors
closely
linked
the
maximum
absorbable
dose
required
provide
appropriate
plasma
levels
of
drugs.
Among
various
strategies
employed
enhance
solubility
permeability,
prodrug
design
stands
out
as
a
highly
effective
versatile
approach
for
improving
properties
enabling
optimization
biopharmaceutical
pharmacokinetic
while
mitigating
adverse
effects.
Prodrugs
compounds
with
reduced
or
no
activity
that,
through
bio-reversible
chemical
enzymatic
processes,
release
an
active
parental
drug.
The
application
this
technology
has
led
significant
advancements
in
during
phase,
it
offers
broad
potential
further
development.
Notably,
approximately
13%
drugs
approved
by
U.S.
Food
Drug
Administration
(FDA)
between
2012
2022
were
prodrugs.
In
review
article,
we
will
explore
describing
examples
market
We
also
describe
use
optimize
PROteolysis
TArgeting
Chimeras
(PROTACs)
using
conjugation
technologies.
highlight
some
new
technologies
prodrugs
enrich
properties,
contributing
developing
safe
Angewandte Chemie International Edition,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 6, 2025
Z-DNA
binding
protein
1
(ZBP1)
has
emerged
as
a
critical
pathogen-sensing
that
upon
activation,
triggers
necroptotic
signaling
cascades,
leading
to
potent
inflammatory
response
and
potentially
causing
significant
tissue
damage.
However,
available
drugs
specifically
developed
for
the
effective
inhibition
or
degradation
of
ZBP1
is
still
lacking
so
far.
In
this
study,
we
covalent
recognition-based
PROTAC
(C-PROTAC)
molecule
ZBP1.
It
consists
DNA
aptamer
recognition
moiety
an
E3
enzyme-recruiting
unit,
connected
by
linker
containing
N-acyl-N-alkyl
sulfonamides
(NASA)
groups.
The
binds
ZBP1,
while
NASA-containing
facilitates
formation
bond
between
target
protein.
ligase-recruiting
unit
then
directs
ubiquitin-proteasome
system
degrade
ZBP1-PROTAC
complex.
This
approach
combines
high
specificity
aptamers
with
efficiency
degradation-inducing
capabilities
PROTACs,
providing
powerful
tool
targeted
degradation.
successful
application
technology
highlights
its
potential
selective
elimination
disease-associated
proteins
development
novel
therapeutic
strategies.