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.
Signal Transduction and Targeted Therapy,
Год журнала:
2022,
Номер
7(1)
Опубликована: Апрель 4, 2022
Abstract
Traditional
drug
discovery
mainly
focuses
on
direct
regulation
of
protein
activity.
The
development
and
application
activity
modulators,
particularly
inhibitors,
has
been
the
mainstream
in
development.
In
recent
years,
PROteolysis
TArgeting
Chimeras
(PROTAC)
technology
emerged
as
one
most
promising
approaches
to
remove
specific
disease-associated
proteins
by
exploiting
cells’
own
destruction
machinery.
addition
PROTAC,
many
different
targeted
degradation
(TPD)
strategies
including,
but
not
limited
to,
molecular
glue,
Lysosome-Targeting
Chimaera
(LYTAC),
Antibody-based
PROTAC
(AbTAC),
are
emerging.
These
technologies
have
only
greatly
expanded
scope
TPD,
also
provided
fresh
insights
into
discovery.
Here,
we
summarize
advances
major
TPD
technologies,
discuss
their
potential
applications,
hope
provide
a
prime
for
both
biologists
chemists
who
interested
this
vibrant
field.
Chemical Society Reviews,
Год журнала:
2022,
Номер
51(12), С. 5214 - 5236
Опубликована: Янв. 1, 2022
Proteolysis-targeting
chimeras
(PROTACs)
are
heterobifunctional
molecules
consisting
of
one
ligand
that
binds
to
a
protein
interest
(POI)
and
another
can
recruit
an
E3
ubiquitin
ligase.
The
chemically-induced
proximity
between
the
POI
ligase
results
in
ubiquitination
subsequent
degradation
by
ubiquitin-proteasome
system
(UPS).
event-driven
mechanism
action
(MOA)
PROTACs
offers
several
advantages
compared
traditional
occupancy-driven
small
molecule
inhibitors,
such
as
catalytic
nature,
reduced
dosing
frequency,
more
potent
longer-lasting
effect,
added
layer
selectivity
reduce
potential
toxicity,
efficacy
face
drug-resistance
mechanisms,
targeting
nonenzymatic
functions,
expanded
target
space.
Here,
we
highlight
important
milestones
briefly
discuss
lessons
learned
about
targeted
(TPD)
recent
years
conjecture
on
efforts
still
needed
expand
toolbox
for
PROTAC
discovery
ultimately
provide
promising
therapeutics.
Abstract
Proteolysis-targeting
chimeras
(PROTACs)
are
engineered
techniques
for
targeted
protein
degradation.
A
bifunctional
PROTAC
molecule
with
two
covalently-linked
ligands
recruits
target
and
E3
ubiquitin
ligase
together
to
trigger
proteasomal
degradation
of
by
the
ubiquitin-proteasome
system.
has
emerged
as
a
promising
approach
therapy
in
various
diseases,
particularly
cancers.
In
this
review,
we
introduce
principle
development
technology,
well
advantages
PROTACs
over
traditional
anti-cancer
therapies.
Moreover,
summarize
application
targeting
critical
oncoproteins,
provide
guidelines
molecular
design
discuss
challenges
PROTACs.
Signal Transduction and Targeted Therapy,
Год журнала:
2022,
Номер
7(1)
Опубликована: Июнь 9, 2022
Abstract
PROteolysis
TArgeting
Chimeras
(PROTACs)
technology
is
a
new
protein-degradation
strategy
that
has
emerged
in
recent
years.
It
uses
bifunctional
small
molecules
to
induce
the
ubiquitination
and
degradation
of
target
proteins
through
ubiquitin–proteasome
system.
PROTACs
can
not
only
be
used
as
potential
clinical
treatments
for
diseases
such
cancer,
immune
disorders,
viral
infections,
neurodegenerative
diseases,
but
also
provide
unique
chemical
knockdown
tools
biological
research
catalytic,
reversible,
rapid
manner.
In
2019,
our
group
published
review
article
“PROTACs:
great
opportunities
academia
industry”
journal,
summarizing
representative
compounds
reported
before
end
2019.
past
2
years,
entire
field
protein
experienced
development,
including
large
increase
number
papers
on
small-molecule
degraders
have
entered
will
enter
stage.
addition
PROTAC
molecular
glue
technology,
other
technologies
are
developing
rapidly.
this
article,
we
mainly
summarize
related
targets
2020–2021
present
researchers
exciting
developments
degradation.
The
problems
need
solved
briefly
introduced.
Molecular Biomedicine,
Год журнала:
2022,
Номер
3(1)
Опубликована: Дек. 20, 2022
Abstract
Proteolysis
targeting
chimeras
(PROTACs)
technology
has
emerged
as
a
novel
therapeutic
paradigm
in
recent
years.
PROTACs
are
heterobifunctional
molecules
that
degrade
target
proteins
by
hijacking
the
ubiquitin–proteasome
system.
Currently,
about
20–25%
of
all
protein
targets
being
studied,
and
most
works
focus
on
their
enzymatic
functions.
Unlike
small
molecules,
inhibit
whole
biological
function
binding
to
inducing
subsequent
proteasomal
degradation.
compensate
for
limitations
transcription
factors,
nuclear
proteins,
other
scaffolding
difficult
handle
with
traditional
small-molecule
inhibitors.
have
successfully
degraded
diverse
such
BTK,
BRD4,
AR,
ER,
STAT3,
IRAK4,
tau,
etc.
And
ARV-110
ARV-471
exhibited
excellent
efficacy
clinical
II
trials.
However,
what
appropriate
PROTAC
achieve
better
benefits
than
inhibitors
not
fully
understood.
how
rationally
design
an
efficient
optimize
it
be
orally
effective
poses
big
challenges
researchers.
In
this
review,
we
summarize
features
technology,
analyze
detail
general
principles
designing
PROTACs,
discuss
typical
application
different
categories.
addition,
also
introduce
progress
relevant
trial
results
representative
assess
may
face.
Collectively,
our
studies
provide
references
further
PROTACs.
Chemical Society Reviews,
Год журнала:
2022,
Номер
51(19), С. 8216 - 8257
Опубликована: Янв. 1, 2022
This
review
provides
a
comprehensive
overview
of
the
structure-based
design
small-molecule
VHL
ligands
and
their
applications
as
inhibitors
E3
ligase
recruiting
moieties
in
PROTAC
degraders.
Signal Transduction and Targeted Therapy,
Год журнала:
2022,
Номер
7(1)
Опубликована: Окт. 5, 2022
Lung
cancer
is
the
leading
cause
of
cancer-related
death
across
world.
Unlike
lung
adenocarcinoma,
patients
with
squamous
cell
carcinoma
(LSCC)
have
not
benefitted
from
targeted
therapies.
Although
immunotherapy
has
significantly
improved
patients'
outcomes,
relatively
low
response
rate
and
severe
adverse
events
hinder
clinical
application
this
promising
treatment
in
LSCC.
Therefore,
it
vital
importance
to
a
better
understanding
mechanisms
underlying
pathogenesis
LSCC
as
well
inner
connection
among
different
signaling
pathways,
which
will
surely
provide
opportunities
for
more
effective
therapeutic
interventions
In
review,
new
insights
were
given
about
classical
pathways
been
proved
other
types
but
LSCC,
including
PI3K
pathway,
VEGF/VEGFR
signaling,
CDK4/6
pathway.
Other
may
potentials
also
discussed,
FGFR1
EGFR
KEAP1/NRF2
Next,
chromosome
3q,
harbors
two
key
differentiation
markers
SOX2
TP63
discussed
its
related
potential
targets.
We
provided
some
progress
epigenetic
therapies
immune
checkpoints
blockade
(ICB)
Subsequently,
we
outlined
combination
strategies
ICB
Finally,
prospects
challenges
exploration
novel
