Journal of the American Chemical Society,
Год журнала:
2022,
Номер
144(28), С. 12934 - 12941
Опубликована: Июль 5, 2022
Targeted
protein
degradation
approaches
have
been
widely
used
for
degrading
oncogenic
proteins,
providing
a
potentially
promising
therapeutic
strategy
cancer
treatment.
However,
to
targeting
tumor
suppressor
proteins
are
very
limited,
and
only
few
agonists
developed
date.
Here,
we
report
the
development
of
platform
termed
TF-DUBTAC,
which
links
DNA
oligonucleotide
covalent
ligand
deubiquitinase
OTUB1
via
click
reaction,
selectively
stabilize
transcription
factors.
We
three
series
TF-DUBTACs,
namely,
FOXO-DUBTAC,
p53-DUBTAC,
IRF-DUBTAC,
FOXO3A,
p53,
IRF3
in
cells,
respectively,
an
OTUB1-dependent
manner.
These
results
suggest
that
TF-DUBTAC
is
generalizable
achieve
selective
stabilization
factors
as
means
suppress
tumorigenesis.
Medicinal Research Reviews,
Год журнала:
2022,
Номер
42(3), С. 1280 - 1342
Опубликована: Янв. 10, 2022
Abstract
Proteolysis
targeting
chimaeras
(PROTACs)
is
a
cutting
edge
and
rapidly
growing
technique
for
new
drug
discovery
development.
Currently,
the
largest
challenge
in
molecular
design
development
of
PROTACs
efficient
identification
potent
drug‐like
degraders.
This
review
aims
to
comprehensively
summarize
analyse
state‐of‐the‐art
methods
strategies
PROTACs.
We
provide
detailed
illustration
general
principles
tactics
designing
PROTACs,
highlight
representative
case
studies,
discuss
advantages
limitations
these
strategies.
Particularly,
structure‐based
rational
PROTAC
emerging
types
(e.g.,
homo‐PROTACs,
multitargeting
photo‐control
PROTAC‐based
conjugates)
will
be
focused
on.
Journal of the American Chemical Society,
Год журнала:
2023,
Номер
145(16), С. 9334 - 9342
Опубликована: Апрель 17, 2023
Triple-negative
breast
cancer
(TNBC)
is
highly
aggressive
with
a
poor
clinical
prognosis
and
no
targeted
therapy.
The
c-Myc
protein
master
transcription
factor
potential
therapeutic
target
for
TNBC.
In
this
study,
we
develop
PROTAC
(PROteolysis
TArgeting
Chimera)
based
on
TNA
(threose
nucleic
acid)
DNA
that
effectively
targets
degrades
c-Myc.
aptamer
selected
in
vitro
to
bind
the
c-Myc/Max
heterodimer
appended
E-box
sequence
create
high-affinity,
biologically
stable
bivalent
binder.
TNA-E
box-pomalidomide
(TEP)
conjugate
specifically
endogenous
c-Myc/Max,
inhibits
TNBC
cell
proliferation,
sensitizes
cells
cyclin-dependent
kinase
inhibitor
palbociclib
vitro.
mouse
model,
combination
therapy
TEP
potently
suppresses
tumor
growth.
This
study
offers
promising
acid-based
modality
both
chemical
biology
studies
interventions
of
ACS Nano,
Год журнала:
2023,
Номер
17(7), С. 6150 - 6164
Опубликована: Март 21, 2023
The
selective
removal
of
misfolded,
aggregated,
or
aberrantly
overexpressed
protein
plays
an
essential
role
in
maintaining
protein-dominated
biological
processes.
In
parallel,
the
precise
knockout
abnormal
proteins
is
inseparable
from
accurate
identification
within
complex
environments.
Guided
by
these
precepts,
small
molecules,
antibodies,
are
commonly
used
as
recognition
tools
for
developing
targeted
degradation
(TPD)
technology.
Indeed,
TPD
has
shown
tremendous
prospects
chronic
diseases,
rare
cancer
research,
and
other
fields.
Meanwhile,
aptamers
short
RNA
DNA
oligonucleotides
that
can
bind
to
target
with
high
specificity
strong
affinity.
Accordingly,
actively
designing
constructing
this
perspective,
we
provide
a
brief
introduction
technology
its
current
progress,
summarize
application
challenges.
Recent
advances
aptamer-based
reviewed,
together
corresponding
challenges
outlooks.
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Ноя. 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.
Science Bulletin,
Год журнала:
2024,
Номер
69(11), С. 1776 - 1797
Опубликована: Март 29, 2024
Undruggable
targets
typically
refer
to
a
class
of
therapeutic
that
are
difficult
target
through
conventional
methods
or
have
not
yet
been
targeted,
but
great
clinical
significance.
According
statistics,
over
80%
disease-related
pathogenic
proteins
cannot
be
targeted
by
current
treatment
methods.
In
recent
years,
with
the
advancement
basic
research
and
new
technologies,
development
various
technologies
mechanisms
has
brought
perspectives
overcome
challenging
drug
targets.
Among
them,
protein
degradation
technology
is
breakthrough
strategy
for
This
can
specifically
identify
directly
degrade
utilizing
inherent
pathways
within
cells.
form
includes
types
such
as
proteolysis
targeting
chimera
(PROTAC),
molecular
glue,
lysosome-targeting
Chimaera
(LYTAC),
autophagosome-tethering
compound
(ATTEC),
autophagy-targeting
(AUTAC),
(AUTOTAC),
degrader-antibody
conjugate
(DAC).
article
systematically
summarizes
application
in
degraders
Finally,
looks
forward
future
direction
prospects
technology.
Acta Pharmaceutica Sinica B,
Год журнала:
2024,
Номер
14(6), С. 2402 - 2427
Опубликована: Янв. 21, 2024
Targeted
protein
degradation
(TPD)
represented
by
proteolysis
targeting
chimeras
(PROTACs)
marks
a
significant
stride
in
drug
discovery.
A
plethora
of
innovative
technologies
inspired
PROTAC
have
not
only
revolutionized
the
landscape
TPD
but
potential
to
unlock
functionalities
beyond
degradation.
Non-small-molecule-based
approaches
play
an
irreplaceable
role
this
field.
wide
variety
agents
spanning
broad
chemical
spectrum,
including
peptides,
nucleic
acids,
antibodies,
and
even
vaccines,
which
prove
instrumental
overcoming
constraints
conventional
small
molecule
entities
also
provided
rapidly
renewing
paradigms.
Herein
we
summarize
burgeoning
non-small
technological
platforms
PROTACs,
three
major
trajectories,
provide
insights
for
design
strategies
based
on
novel
Journal of the American Chemical Society,
Год журнала:
2022,
Номер
144(49), С. 22622 - 22632
Опубликована: Ноя. 30, 2022
Proteolysis
Targeting
Chimeras
(PROTACs)
are
attractive
therapeutic
modalities
for
degrading
disease-causing
proteins.
While
many
PROTACs
have
been
developed
numerous
protein
targets,
current
small-molecule
PROTAC
approaches
cannot
target
undruggable
proteins
that
do
not
binders.
Here,
we
present
a
novel
approach,
termed
bridged
PROTAC,
which
utilizes
binder
of
the
protein's
binding
partner
to
recruit
complex
into
close
proximity
with
an
E3
ubiquitin
ligase
Applying
this
strategy,
discovered
MS28,
first-in-class
degrader
cyclin
D1,
lacks
binder.
MS28
effectively
degrades
faster
degradation
kinetics
and
superior
efficiency
than
CDK4/6,
through
recruiting
CDK4/6-cyclin
D1
von
Hippel–Lindau
ligase.
also
suppressed
proliferation
cancer
cells
more
CDK4/6
inhibitors
degraders.
Altogether,
strategy
could
provide
generalizable
platform
targeting
