Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(12), P. 9842 - 9856
Published: June 5, 2024
Advancements
in
anticancer
strategies
spotlight
proteolysis
targeting
chimera
(PROTAC)
technology,
yet
it
is
hindered
by
poor
water
solubility
and
bioavailability.
This
study
introduces
a
novel
amphiphilic
PROTAC,
B1-PEG,
synthesized
through
PEGylation
of
an
optimized
PROTAC
molecule,
B1,
to
enhance
its
properties.
B1-PEG
engineered
self-organize
into
micelles
releases
active
form
response
the
tumor-specific
high
GSH
environment.
Comparative
pharmacokinetic
analysis
revealed
B1-PEG's
superior
bioavailability
at
84.8%,
outperforming
unmodified
molecule
B1.
When
tested
H3122
xenograft
mouse
model,
significantly
regressed
tumors,
underscoring
potential
as
formidable
candidate
targeted
cancer
therapy.
Our
findings
offer
promising
direction
for
overcoming
limitations
drug
design.
Journal of the American Chemical Society,
Journal Year:
2023,
Volume and Issue:
145(34), P. 18698 - 18704
Published: Aug. 15, 2023
As
heavy-metal-based
nanoscale
metal–organic
frameworks
(nMOFs)
are
excellent
radiosensitizers
for
radiotherapy
via
enhanced
energy
deposition
and
reactive
oxygen
species
(ROS)
generation,
we
hypothesize
that
nMOFs
with
covalently
conjugated
X-ray
triggerable
prodrugs
can
harness
the
ROS
on-demand
release
of
chemotherapeutics
chemoradiotherapy.
Herein,
report
design
a
novel
nMOF,
Hf-TP-SN,
an
X-ray-triggerable
7-ethyl-10-hydroxycamptothecin
(SN38)
prodrug
synergistic
chemotherapy.
Upon
irradiation,
electron-dense
Hf12
secondary
building
units
serve
as
to
enhance
hydroxyl
radical
generation
triggered
SN38
hydroxylation
3,5-dimethoxylbenzyl
carbonate
followed
by
1,4-elimination,
leading
5-fold
higher
from
Hf-TP-SN
than
its
molecular
counterpart.
result,
plus
radiation
induces
significant
cytotoxicity
cancer
cells
efficiently
inhibits
tumor
growth
in
colon
breast
mouse
models.
Journal of the American Chemical Society,
Journal Year:
2023,
Volume and Issue:
145(30), P. 16642 - 16649
Published: July 21, 2023
Confining
the
protein
degradation
activity
of
proteolysis-targeting
chimera
(PROTAC)
to
cancer
lesions
ensures
precision
treatment.
However,
it
still
remains
challenging
precisely
control
PROTAC
function
in
tumor
regions
vivo.
We
herein
describe
a
near-infrared
(NIR)
photoactivatable
nano-PROTAC
(NAP)
for
remote-controllable
proteolysis
tumor-bearing
mice.
NAP
is
formed
by
molecular
self-assembly
from
an
amphiphilic
conjugate
linked
with
NIR
photosensitizer
through
singlet
oxygen
(1O2)-cleavable
linker.
The
initially
silenced
but
can
be
remotely
switched
on
upon
photoirradiation
generate
1O2
photosensitizer.
demonstrated
that
enabled
tumor-specific
bromodomain-containing
4
(BRD4)
light-instructed
manner.
This
combination
photodynamic
therapy
(PDT)
elicited
effective
suppression
growth.
work
thus
presents
novel
approach
spatiotemporal
over
targeted
PROTAC.
Journal of Medicinal Chemistry,
Journal Year:
2023,
Volume and Issue:
66(13), P. 8428 - 8440
Published: June 15, 2023
Proteolysis-targeting
chimera
(PROTAC)
technology
represents
a
novel
and
promising
modality
for
targeted
protein
degradation
with
transformative
implications
the
clinical
management
of
various
diseases.
Despite
notable
advantages,
possibility
on-target
off-tumor
toxicity
in
healthy
cells
critical
challenge
to
applications
cancer
treatment.
Researchers
are
currently
exploring
strategies
enhance
activity
cell-selective
manner
minimize
undesirable
side
effects.
In
this
Perspective,
we
highlight
innovative
approaches
prodrug-based
PROTACs
(pro-PROTACs)
that
facilitate
tumor-targeted
release.
The
development
such
may
further
expand
range
potential
PROTAC
within
drug
development.
Molecular Cancer,
Journal Year:
2024,
Volume and Issue:
23(1)
Published: May 21, 2024
Abstract
Proteolysis-targeting
chimeras
(PROTACs)
technology
has
garnered
significant
attention
over
the
last
10
years,
representing
a
burgeoning
therapeutic
approach
with
potential
to
address
pathogenic
proteins
that
have
historically
posed
challenges
for
traditional
small-molecule
inhibitors.
PROTACs
exploit
endogenous
E3
ubiquitin
ligases
facilitate
degradation
of
interest
(POIs)
through
ubiquitin–proteasome
system
(UPS)
in
cyclic
catalytic
manner.
Despite
recent
endeavors
advance
utilization
clinical
settings,
majority
fail
progress
beyond
preclinical
phase
drug
development.
There
are
multiple
factors
impeding
market
entry
PROTACs,
insufficiently
precise
favorable
POIs
standing
out
as
one
most
formidable
obstacles.
Recently,
there
been
exploration
new-generation
advanced
including
PROTAC
prodrugs,
biomacromolecule-PROTAC
conjugates,
and
nano-PROTACs,
improve
vivo
efficacy
PROTACs.
These
improved
possess
capability
mitigate
undesirable
physicochemical
characteristics
inherent
thereby
enhancing
their
targetability
reducing
off-target
side
effects.
The
will
mark
pivotal
turning
point
realm
targeted
protein
degradation.
In
this
comprehensive
review,
we
meticulously
summarized
state-of-the-art
advancements
achieved
by
these
cutting-edge
elucidated
underlying
design
principles,
deliberated
upon
prevailing
encountered,
provided
an
insightful
outlook
on
future
prospects
within
field.
Signal Transduction and Targeted Therapy,
Journal Year:
2024,
Volume and Issue:
9(1)
Published: Nov. 26, 2024
Epigenetics
governs
a
chromatin
state
regulatory
system
through
five
key
mechanisms:
DNA
modification,
histone
RNA
remodeling,
and
non-coding
regulation.
These
mechanisms
their
associated
enzymes
convey
genetic
information
independently
of
base
sequences,
playing
essential
roles
in
organismal
development
homeostasis.
Conversely,
disruptions
epigenetic
landscapes
critically
influence
the
pathogenesis
various
human
diseases.
This
understanding
has
laid
robust
theoretical
groundwork
for
developing
drugs
that
target
epigenetics-modifying
pathological
conditions.
Over
past
two
decades,
growing
array
small
molecule
targeting
such
as
methyltransferase,
deacetylase,
isocitrate
dehydrogenase,
enhancer
zeste
homolog
2,
have
been
thoroughly
investigated
implemented
therapeutic
options,
particularly
oncology.
Additionally,
numerous
epigenetics-targeted
are
undergoing
clinical
trials,
offering
promising
prospects
benefits.
review
delineates
epigenetics
physiological
contexts
underscores
pioneering
studies
on
discovery
implementation
drugs.
include
inhibitors,
agonists,
degraders,
multitarget
agents,
aiming
to
identify
practical
challenges
avenues
future
research.
Ultimately,
this
aims
deepen
epigenetics-oriented
strategies
further
application
settings.
Signal Transduction and Targeted Therapy,
Journal Year:
2024,
Volume and Issue:
9(1)
Published: Nov. 6, 2024
Abstract
Targeted
protein
degradation
(TPD)
represents
a
revolutionary
therapeutic
strategy
in
disease
management,
providing
stark
contrast
to
traditional
approaches
like
small
molecule
inhibitors
that
primarily
focus
on
inhibiting
function.
This
advanced
technology
capitalizes
the
cell’s
intrinsic
proteolytic
systems,
including
proteasome
and
lysosomal
pathways,
selectively
eliminate
disease-causing
proteins.
TPD
not
only
enhances
efficacy
of
treatments
but
also
expands
scope
applications.
Despite
its
considerable
potential,
faces
challenges
related
properties
drugs
their
rational
design.
review
thoroughly
explores
mechanisms
clinical
advancements
TPD,
from
initial
conceptualization
practical
implementation,
with
particular
proteolysis-targeting
chimeras
molecular
glues.
In
addition,
delves
into
emerging
technologies
methodologies
aimed
at
addressing
these
enhancing
efficacy.
We
discuss
significant
trials
highlight
promising
outcomes
associated
drugs,
illustrating
potential
transform
treatment
landscape.
Furthermore,
considers
benefits
combining
other
therapies
enhance
overall
effectiveness
overcome
drug
resistance.
The
future
directions
applications
are
explored,
presenting
an
optimistic
perspective
further
innovations.
By
offering
comprehensive
overview
current
innovations
faced,
this
assesses
transformative
revolutionizing
development
setting
stage
for
new
era
medical
therapy.
