Journal of the American Chemical Society,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 22, 2024
Stress
granules
(SGs)
are
membraneless
cytoplasmic
compartments
that
form
in
response
to
stress
stimuli.
In
these
compartments,
most
translation
factors
stall,
except
for
activating
transcription
factor
4
(ATF4),
which
is
preferentially
translated
ensure
cell
survival
under
stressful
conditions.
Cancer
cells
encounter
various
conditions
the
tumor
microenvironment
during
tumorigenesis;
however,
how
they
exploit
pro-survival
effects
of
ATF4
SGs
remains
unclear.
G3BP1/2
central
nodes
SG
network,
regulating
dynamics.
this
study,
we
designed
two
small
molecules,
#129
and
PROTAC
(Proteolysis
Targeting
Chimera)
degrader
129
(PT-129),
specifically
target
NTF2L
domain
G3BP1/2,
a
crucial
hub
protein
RNA
interactions.
These
compounds
inhibit
formation
stressed
disassemble
pre-existing
granules.
Furthermore,
pharmacological
inhibition
by
PT-129
suppressed
fibroblast-mediated
cancer
growth
vitro
reduced
vivo.
Mechanistically,
facilitates
delivery
from
fibroblasts
via
migracytosis,
primary
mediator
fibroblast-associated
growth.
PT-129-mediated
disassembly
disrupts
delivery,
thereby
preventing
proliferation.
compounds,
therefore,
represent
powerful
tools
gaining
molecular
insights
into
hold
promise
therapeutic
interventions
modulating
granule
International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(16), P. 8984 - 8984
Published: Aug. 18, 2024
CC
chemokine
receptor
2
(CCR2)
has
been
linked
to
many
inflammatory
and
immune
diseases,
making
it
a
relevant
drug
target.
Yet,
all
CCR2
antagonists
developed
so
far
have
failed
in
clinical
trials;
thus,
novel
strategies
are
needed
target
this
receptor.
Targeted
protein
degradation
represents
approach
inhibit
function
by
hijacking
the
cellular
machinery,
such
as
proteasome,
degrade
of
interest.
Here,
we
aimed
determine
amenability
chemically
induced
using
fusion
containing
HaloTag7
HiBiT
tag
(CCR2-HaloTag-HiBiT).
After
characterization
construct,
used
luminescence-based
assays
immunofluorescence
quantify
levels,
well
label-free,
phenotypic
assay
investigate
functional
effect
degradation.
Treatment
with
HaloPROTAC3,
which
selectively
degrades
HaloTag
proteins,
led
concentration-
time-dependent
CCR2-HaloTag-HiBiT.
HaloPROTAC3
via
was
fully
blocked
proteasomal
inhibitors.
Finally,
showed
that
CCR2-HaloTag-HiBiT
leads
reduced
response
after
agonist
stimulation.
Overall,
our
results
indicate
is
amenable
targeted
degradation,
paving
way
for
future
development
chemical
degraders.
Journal of the American Chemical Society,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 20, 2024
Molecular
glues
are
promising
protein-degrading
agents
that
hold
great
therapeutic
potential
but
face
significant
challenges
in
rational
design,
effective
synthesis,
and
precise
targeting
of
tumor
sites.
In
this
study,
we
first
overcame
some
these
limitations
by
introducing
a
fumarate-based
molecular
glue
handle
onto
specific
ligands
kinases
(TBK1,
FGFR,
Bcr-Abl),
resulting
the
degradation
important
cancer
targets.
Despite
broad
applicability
strategy,
unexpectedly
discovered
potent
widespread
cytotoxicity
across
various
cell
lines,
including
noncancerous
ones,
rendering
it
less
therapy.
To
address
critical
issue,
next
developed
self-assembled
nanoparticle-based
(nano-mGlu)
based
on
one
newly
Bcr-Abl-degrading
(H1-mGlu).
We
showed
nano-mGlu
(named
Cle-NP)
was
able
to
release
H1-mGlu
vitro
presence
high
concentration
GSH
or
H2O2
(commonly
found
microenvironment).
Subsequent
vivo
antitumor
studies
with
K562-xenografted
mouse
model
indicated
Cle-NP
highly
tumor-specific
endogenous
Bcr-Abl
expressed
K562
cells,
leading
eventual
regression
while
maintaining
good
biosafety
profiles.
With
key
advantages
generality
targeted
delivery
(e.g.,
H1-mGlu),
activity
partially
induced
target-specific
degradation,
minimized
collateral
damage
healthy
tissues,
our
strategy
thus
provides
novel
approach
might
promise
for
personalized
Journal of the American Chemical Society,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 22, 2024
Stress
granules
(SGs)
are
membraneless
cytoplasmic
compartments
that
form
in
response
to
stress
stimuli.
In
these
compartments,
most
translation
factors
stall,
except
for
activating
transcription
factor
4
(ATF4),
which
is
preferentially
translated
ensure
cell
survival
under
stressful
conditions.
Cancer
cells
encounter
various
conditions
the
tumor
microenvironment
during
tumorigenesis;
however,
how
they
exploit
pro-survival
effects
of
ATF4
SGs
remains
unclear.
G3BP1/2
central
nodes
SG
network,
regulating
dynamics.
this
study,
we
designed
two
small
molecules,
#129
and
PROTAC
(Proteolysis
Targeting
Chimera)
degrader
129
(PT-129),
specifically
target
NTF2L
domain
G3BP1/2,
a
crucial
hub
protein
RNA
interactions.
These
compounds
inhibit
formation
stressed
disassemble
pre-existing
granules.
Furthermore,
pharmacological
inhibition
by
PT-129
suppressed
fibroblast-mediated
cancer
growth
vitro
reduced
vivo.
Mechanistically,
facilitates
delivery
from
fibroblasts
via
migracytosis,
primary
mediator
fibroblast-associated
growth.
PT-129-mediated
disassembly
disrupts
delivery,
thereby
preventing
proliferation.
compounds,
therefore,
represent
powerful
tools
gaining
molecular
insights
into
hold
promise
therapeutic
interventions
modulating
granule
