Burger's Medicinal Chemistry and Drug Discovery,
Год журнала:
2025,
Номер
unknown, С. 1 - 45
Опубликована: Май 26, 2025
Abstract
The
field
of
targeted
protein
degradation
(TPD)
has
expanded
rapidly
in
the
last
decade.
However,
only
a
handful
metal‐dependent
enzymes
(metalloenzymes)
have
been
target
these
efforts.
chapter
gives
an
overview
TPD
as
it
applied
to
metalloenzymes
and
highlights
key
findings.
relevant
bioinorganic
chemistry
approaches,
including
metal‐binding
pharmacophores
(MBPs)
used
degraders,
will
be
particular
emphasis
this
review.
Chemical Reviews,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 17, 2025
The
nascent
field
of
targeted
protein
degradation
(TPD)
could
revolutionize
biomedicine
due
to
the
ability
degrader
molecules
selectively
modulate
disease-relevant
proteins.
A
key
limitation
broad
application
TPD
is
its
dependence
on
small-molecule
ligands
target
proteins
interest.
This
leaves
unstructured
or
those
lacking
defined
cavities
for
binding
out
scope
many
technologies.
use
proteins,
peptides,
and
nucleic
acids
(otherwise
known
as
"biologics")
protein-targeting
moieties
in
degraders
addresses
this
limitation.
In
following
sections,
we
provide
a
comprehensive
critical
review
studies
that
have
used
peptides
mediate
hence
functional
control
otherwise
challenging
targets.
We
describe
existing
platforms
protein/peptide-based
ligand
identification
drug
delivery
systems
might
be
exploited
biologic-based
degraders.
Throughout
Review,
underscore
successes,
challenges,
opportunities
using
protein-based
chemical
biology
tools
spur
discoveries,
elucidate
mechanisms,
act
new
therapeutic
modality.
ACS Omega,
Год журнала:
2025,
Номер
10(5), С. 4745 - 4753
Опубликована: Янв. 30, 2025
Among
the
various
strategies
being
developed
in
field
of
protein
degraders,
HyTags
remain
relatively
underexplored,
despite
their
advantages
over
PROTACs.
Their
synthesis
typically
involves
multistep
procedures,
including
use
coupling
reagents
and
protection/deprotection
steps.
To
develop
a
more
sustainable
streamlined
approach,
we
designed
versatile
multicomponent
platform
that
generates
with
diverse
linkers
hydrophobic
moieties
high
yields.
Using
(+)-JQ1
as
POI
ligand,
synthesized
series
BRD4-targeting
discovered
compound
23
induces
degradation
BRD4
via
autophagy-lysosome
pathway
through
ER
stress.
This
finding
further
supports
valuable
application
this
synthetic
methodology
search
for
effective
degraders.
RSC Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
As
the
field
of
targeted
protein
degradation
has
advanced,
it
expanded
beyond
traditional
recruitment
to
E3
substrate
receptors
new
approaches
involving
a
variety
other
components
within
ubiquitin
proteasome
system.
Cell Death and Disease,
Год журнала:
2025,
Номер
16(1)
Опубликована: Март 21, 2025
Abstract
Signal
transducer
and
activator
of
transcription
3
(STAT3)
is
widely
recognized
as
an
attractive
target
for
cancer
therapy
due
to
its
significant
role
in
the
initiation
progression
tumorigenesis.
However,
existing
STAT3
inhibitors
have
suffered
from
drawbacks
including
poor
efficacy,
limited
specificity,
undesirable
off-target
effects,
challenging
nature
identifying
active
sites
or
allosteric
regulatory
pockets
on
amenable
small-molecule
inhibition.
In
response
these
obstacles,
we
utilize
innovative
proteolysis
targeting
chimera
(PROTAC)
technology
create
a
highly
specific
decoy-targeted
protein
degradation
system
protein,
termed
D-PROTAC.
This
fuses
DNA
decoy
that
targets
with
E3
ligase
ligand,
utilizing
click
chemistry
approach.
Experimental
results
demonstrate
D-PROTAC
efficiently
mediates
across
various
cell
types,
leading
downregulation
crucial
downstream
targets,
inhibiting
tumor
growth,
triggering
cycle
arrest
apoptosis,
suppressing
immune
evasion.
Furthermore,
capable
achieving
suppression
xenograft
models.
Overall,
our
research
validates
can
successfully
eliminate
“undruggable”
STAT3,
showcasing
specificity
potent
antitumor
effects.
strategy
will
suggest
promising
avenue
development
targeted
therapies
against
critical
functions
human
cancers
potentially
other
diseases.
Advanced Science,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 30, 2025
Recent
advances
in
lysosome-targeting
degradation
technologies
have
introduced
strategies
to
regulate
therapeutic
membrane
proteins
(MPs),
potentially
transforming
treatment
paradigms.
However,
challenges
persist,
including
limited
precision
due
the
broad
distribution
of
receptors
(LTRs),
as
well
high
cost
and
complexity
recombinant
protein
production
or
chemical
synthesis.
Herein,
it
identifies
sortilin
a
promising
LTR,
highly
expressed
malignancies
but
minimally
present
healthy
tissues
outside
nervous
system.
Using
AlphaFold-Multimer,
screened
for
specific
non-endogenous
binder
developed
modular,
mRNA-encoded
lysosomal
targeting
chimera
(MedTAC)
strategy,
enabling
rapid
design
precise
oncogenic
MPs.
In
breast
cancer-bearing
mouse
model,
single
low
dose
MedTACPTK7
(0.5
mg
kg-1)
reduced
tyrosine
kinase-7
(PTK7)
levels
by
up
80%
within
24
h,
with
sustained
44%
at
72
demonstrating
excellent
pharmacokinetics.
significantly
extended
survival
over
50
days
without
systemic
toxicity,
compared
20-30
controls.
This
MedTAC
strategy
establishes
selective
efficient
shuttle
targeted
degradation,
offering
scalable,
rapidly
producible
platform
biochemical
research
applications.
RSC Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
Hetero-bispecific
degraders,
including
PROTACs,
Pep-TACs,
aptamers,
nanoparticles,
and
antibody-based
constructs
enable
selective
membrane
protein
degradation
by
recruiting
targets
to
proteasomal
or
lysosomal
pathways.
