bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Фев. 15, 2024
Abstract
Alkenyl
oxindoles
have
been
characterized
as
autophagosome-tethering
compounds
(ATTECs),
which
can
target
mutant
huntingtin
protein
(mHTT)
for
lysosomal
degradation.
In
order
to
expand
the
application
of
alkenyl
targeted
degradation,
we
designed
and
synthesized
a
series
hetero-bifunctional
by
conjugating
different
with
BRD4
inhibitor
JQ1.
Through
structure-activity
relationship
study,
successfully
developed
JQ1-alkenyl
oxindole
conjugates
that
potently
degrade
BRD4.
Unexpectedly,
found
these
molecules
through
ubiquitin-proteasome
system,
rather
than
autophagy-lysosomal
pathway.
Using
pooled
CRISPR
interference
(CRISPRi)
screening,
revealed
recruit
E3
ubiquitin
ligase
complex
CRL4
DCAF11
substrate
Furthermore,
validated
most
potent
molecule
HL435
promising
drug-like
lead
compound
exert
antitumor
activity
both
in
vitro
vivo
.
Our
research
provides
new
employable
PROTAC
moieties
providing
possibilities
drug
discovery.
Pharmaceuticals,
Год журнала:
2024,
Номер
17(4), С. 494 - 494
Опубликована: Апрель 12, 2024
Proteolysis-targeting
chimeras
(PROTACs)
are
an
emerging
therapeutic
modality
that
show
promise
to
open
a
target
space
not
accessible
conventional
small
molecules
via
degradation-based
mechanism.
PROTAC
degraders,
due
their
bifunctional
nature,
which
is
categorized
as
‘beyond
the
Rule
of
Five’,
have
gained
attention
distinctive
approach
for
oral
administration
in
clinical
settings.
However,
development
PROTACs
with
adequate
bioavailability
remains
significant
hurdle,
largely
large
size
and
less
than
ideal
physical
chemical
properties.
This
review
encapsulates
latest
advancements
orally
delivered
entered
evaluation
well
developments
highlighted
recent
scholarly
articles.
The
insights
methodologies
elaborated
upon
this
could
be
instrumental
supporting
discovery
refinement
novel
degraders
aimed
at
treatment
various
human
cancers.
Expert Opinion on Therapeutic Targets,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 23, 2025
Introduction
Transcription
factors
(TFs)
are
master
regulators
of
cellular
function
and
orchestrate
diverse
signaling
pathways
processes.
Acting
as
convergence
points
pathways,
they
integrate
extracellular
stimuli
with
intracellular
responses
to
regulate
cell
functions.
Dysregulation
TFs
drives
tumorigenesis
including
proliferation,
drug
resistance,
immune
evasion
multiple
myeloma
(MM),
the
second
most-common
hematologic
malignancy.
International Journal of Molecular Sciences,
Год журнала:
2023,
Номер
24(22), С. 16346 - 16346
Опубликована: Ноя. 15, 2023
Sarcomas
are
heterogeneous
bone
and
soft
tissue
cancers
representing
the
second
most
common
tumor
type
in
children
adolescents.
Histology
genetic
profiling
discovered
more
than
100
subtypes,
which
characterized
by
peculiar
molecular
vulnerabilities.
However,
limited
therapeutic
options
exist
beyond
standard
therapy
clinical
benefits
from
targeted
therapies
were
observed
only
a
minority
of
patients
with
sarcomas.
The
rarity
these
tumors,
paucity
actionable
mutations,
limitations
chemical
composition
current
hindered
use
approaches
Targeted
protein
degradation
(TPD)
is
an
innovative
pharmacological
modality
to
directly
alter
abundance
promising
potential
cancer,
even
for
undruggable
proteins.
TPD
based
on
small
molecules
called
degraders
or
proteolysis-targeting
chimeras
(PROTACs),
trigger
ubiquitin-dependent
interest.
In
this
review,
we
will
discuss
major
features
PROTAC
PROTAC-derived
systems
target
validation
cancer
treatment
focus
overcome
issues
connected
sarcomas,
including
drug
resistance,
specificity,
targets.
A
deeper
understanding
strategies
might
provide
new
fuel
drive
personalized
medicine
Autophagy-targeting
chimera
(AUTAC)
has
emerged
as
a
powerful
modality
that
can
selectively
degrade
tumor-related
pathogenic
proteins,
but
its
low
bioavailability
and
nonspecific
distribution
significantly
restrict
their
therapeutic
efficacy.
Inspired
by
the
guanine
structure
of
AUTAC
molecules,
we
here
report
supramolecular
artificial
Nano-AUTACs
(GM
NPs)
engineered
molecule
GN
[an
indoleamine
2,3-dioxygenase
(IDO)
degrader]
nucleoside
analog
methotrexate
(MTX)
through
interactions
for
tumor-specific
protein
degradation.
Their
nanostructures
allow
precise
localization
delivery
into
cancer
cells,
where
intracellular
acidic
environment
disrupt
to
release
MTX
eradicating
tumor
modulating
tumor-associated
macrophages,
activating
dendritic
inducing
autophagy.
Specifically,
induced
autophagy
facilitates
released
degrading
immunosuppressive
IDO
further
enhance
effector
T
cell
activity
inhibit
growth
metastasis.
This
study
offers
unique
strategy
building
nanoplatform
advance
field
in
immunotherapy.
