Targeting STAT3 for Cancer Therapy: Focusing on Y705, S727, or Dual Inhibition?
Cancers,
Год журнала:
2025,
Номер
17(5), С. 755 - 755
Опубликована: Фев. 23, 2025
Signal
Transducer
and
Activator
of
Transcription
3
(STAT3)
is
a
transcription
factor
that
strongly
implicated
in
various
cancers.
In
its
canonical
signaling
pathway,
Janus
kinases
(JAKs)
phosphorylate
STAT3
at
the
Y705
residue
response
to
cytokines
or
growth
factors,
with
pY705
serving
as
key
marker
oncogenic
activity.
Elevated
levels
correlate
poor
prognosis,
numerous
small-molecule
inhibitors
have
been
developed
block
this
phosphorylation
site.
More
recently,
S727
(pS727)
has
emerged
critical
contributor
STAT3-mediated
oncogenesis,
particularly
due
role
mitochondrial
translocation.
Evidence
suggests
pS727
may
even
surpass
driving
These
findings
prompt
an
important
question:
Which
should
be
prioritized
for
effective
inhibition
cancer
therapy?
This
review
compiles
critically
analyzes
current
literature
on
targeting
and/or
pS727,
evaluating
their
therapeutic
efficacy
vitro,
vivo,
clinical
trials.
We
assess
unique
effects
each
downstream
signaling,
toxicity,
outcomes.
Our
analysis
indicates
both
achieve
greatest
effectiveness.
However,
associated
higher
toxicity
risks.
Comprehensive
evaluation
underscores
importance
maximum
benefit.
The
also
shows
co-targeting
increase
overall
efficacy.
approached
lower
affinity
minimize
enhance
feasibility
dual-targeting
strategies.
Язык: Английский
A Comprehensive Primer and Review of PROTACs and Their In Silico Design
Computer Methods and Programs in Biomedicine,
Год журнала:
2025,
Номер
264, С. 108687 - 108687
Опубликована: Фев. 27, 2025
Язык: Английский
A PDE4 shortform degrader: a first in isoform‐specific PDE4 inhibition
FEBS Journal,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 7, 2025
Although
phosphodiesterase
4
(PDE4)
inhibitors
have
reached
the
clinic,
their
lack
of
selectivity
for
PDE4
enzyme
isoforms
leads
to
documented
side
effects.
Building
in
has
proved
difficult
because
all
enzymes
share
highly
conserved
catalytic
domains.
The
report
by
Sin
et
al.
describes
a
novel
approach
which
potent
proteolysis
targeting
chimera
(PROTAC)
selectively
promotes
degradation
small
subset
(i.e.,
"short
forms")
and
impacts
inflammatory
events
regulated
these
enzymes.
This
offers
unparalleled
selectivity,
potency,
could
represent
dawn
new
pharmacology
selective
regulation
cyclic
AMP
(cAMP)
signaling.
Язык: Английский
Targeted Protein Degradation by KLHDC2 Ligands Identified by High Throughput Screening
Опубликована: Май 9, 2025
Abstract
Proteolysis
targeting
chimeras
(PROTACs)
enable
the
selective
and
sub-stoichiometric
elimination
of
pathological
proteins,
yet
only
two
E3
ligases
are
routinely
used
for
this
purpose.
Here,
we
expand
repertoire
PROTAC
compatible
by
identifying
a
novel
small
molecule
scaffold
ubiquitin
ligase
KLHDC2
using
fluorescence
polarization-based
high
throughput
screen.
We
highlight
utility
ligand
with
synthesis
PROTACs
capable
potently
degrading
BRD4
in
cells.
This
work
affords
additional
chemical
matter
suggests
practical
approach
binders
screening.
Язык: Английский
Targeted Protein Degradation by KLHDC2 Ligands Identified by High Throughput Screening
Опубликована: Май 9, 2025
Abstract
Proteolysis
targeting
chimeras
(PROTACs)
enable
the
selective
and
sub-stoichiometric
elimination
of
pathological
proteins,
yet
only
two
E3
ligases
are
routinely
used
for
this
purpose.
Here,
we
expand
repertoire
PROTAC
compatible
by
identifying
a
novel
small
molecule
scaffold
ubiquitin
ligase
KLHDC2
using
fluorescence
polarization-based
high
throughput
screen.
We
highlight
utility
ligand
with
synthesis
PROTACs
capable
potently
degrading
BRD4
in
cells.
This
work
affords
additional
chemical
matter
suggests
practical
approach
binders
screening.
Язык: Английский
Negative Immune Checkpoint Inhibitors
Pharmaceutics,
Год журнала:
2025,
Номер
17(6), С. 713 - 713
Опубликована: Май 28, 2025
Checkpoint
inhibitors
are
a
modern
therapeutic
approach
for
treating
various
types
of
cancer,
metabolic
diseases,
and
chronic
infections.
The
main
goal
this
therapy
is
to
specifically
unlock
the
immune
system,
allowing
it
recognize
eliminate
cancer
cells
or
pathogens,
primarily
through
activation
T
lymphocytes.
Monoclonal
antibodies
used
in
treatment
cancers,
such
as
pembrolizumab
(Keytruda),
nivolumab
(Opdivo),
ipilimumab
(Yervoy),
carry
several
limitations,
due
their
large
molecular
size.
challenges
include
limited
tissue
penetration,
long
half-life
body,
risk
autoimmune
responses.
Compared
antibodies,
small-molecule
peptide
offer
significant
advantages
related
structure.
These
drugs
demonstrate
better
ability
penetrate
hard-to-reach
areas,
tumor
microenvironments,
can
be
administered
orally,
often
show
lower
immunogenicity.
A
new
generation
PROTACs,
which
combine
direct
proteins
degradation
with
action
checkpoint
inhibitors,
contributing
elimination
responsible
suppressing
response.
This
publication
describes
PROTAC
molecules
targeting
negative
checkpoints—CTLA-4,
PD-1,
VISTA,
TIM-3,
BTLA-4,
LAG-3,
TIGIT.
Язык: Английский