Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(4), С. 2466 - 2486
Опубликована: Фев. 5, 2024
Adenoviral
E1A
binding
protein
300
kDa
(p300)
and
its
closely
related
paralog
CREB
(CBP)
are
promising
therapeutic
targets
for
human
cancer.
Here,
we
report
the
first
discovery
of
novel
potent
small-molecule
PROTAC
degraders
p300/CBP
against
hepatocellular
carcinoma
(HCC),
one
most
common
solid
tumors.
Based
upon
clinical
bromodomain
inhibitor
CCS1477,
a
conformational
restriction
strategy
was
used
to
optimize
linker
generate
series
PROTACs,
culminating
in
identification
QC-182.
This
compound
effectively
induces
degradation
SK-HEP-1
HCC
cells
dose-,
time-,
ubiquitin-proteasome
system-dependent
manner.
QC-182
significantly
downregulates
p300/CBP-associated
transcriptome
cells,
leading
more
cell
growth
inhibition
compared
parental
inhibitors
reported
degrader
dCBP-1.
Notably,
potently
depletes
proteins
mouse
xenograft
tumor
tissue.
is
lead
toward
development
p300/CBP-targeted
therapy.
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.
Frontiers in Cell and Developmental Biology,
Год журнала:
2022,
Номер
10
Опубликована: Апрель 25, 2022
Cancer
drug
resistance
presents
a
major
barrier
to
continued
successful
treatment
of
malignancies.
Current
therapies
inhibiting
proteins
indicated
in
cancer
progression
are
consistently
found
lose
efficacy
as
result
acquired
resistance,
often
caused
by
mutated
or
overexpressed
protein
targets.
By
hijacking
the
cellular
ubiquitin-proteasome
degradation
machinery,
proteolysis-targeting
chimeras
(PROTACs)
offer
an
alternative
therapeutic
modality
treatments
with
various
potential
advantages.
PROTACs
specific
for
number
known
targets
have
been
developed
last
5
years,
which
present
new
options
remission
patients
previously
untreatable
malignancies
and
provide
foundation
future-generation
compounds.
One
notable
advantage
PROTACs,
supported
evidence
from
recent
studies,
is
that
they
can
overcome
some
mechanisms
traditional
targeted
therapies.
More
recently,
groups
begun
researching
use
successfully
degrade
conferring
against
first-line
treatments.
In
this
review,
we
focus
on
analyzing
developments
geared
towards
confer
it
search
Clinical and Translational Medicine,
Год журнала:
2023,
Номер
13(3)
Опубликована: Март 1, 2023
Abstract
Ubiquitination
is
one
of
the
most
important
post‐translational
modifications
which
plays
a
significant
role
in
conserving
homeostasis
cellular
proteins.
In
ubiquitination
process,
ubiquitin
conjugated
to
target
protein
substrates
for
degradation,
translocation
or
activation,
dysregulation
linked
several
diseases
including
various
types
cancers.
E3
ligases
are
regarded
as
influential
enzyme
owing
their
ability
select,
bind
and
recruit
ubiquitination.
particular,
pivotal
cancer
hallmarks
pathways
where
they
serve
tumour
promoters
suppressors.
The
specificity
coupled
with
implication
engendered
development
compounds
that
specifically
therapy.
this
review,
we
highlight
such
sustained
proliferation
via
cell
cycle
progression,
immune
evasion
promoting
inflammation,
apoptosis.
addition,
summarise
application
small
treatment
along
significance
targeting
potential
Chemical Reviews,
Год журнала:
2023,
Номер
123(12), С. 7782 - 7853
Опубликована: Май 15, 2023
The
high
selectivity
and
affinity
of
antibodies
toward
their
antigens
have
made
them
a
highly
valuable
tool
in
disease
therapy,
diagnosis,
basic
research.
A
plethora
chemical
genetic
approaches
been
devised
to
make
accessible
more
"undruggable"
targets
equipped
with
new
functions
illustrating
or
regulating
biological
processes
precisely.
In
this
Review,
addition
introducing
how
naked
various
antibody
conjugates
(such
as
antibody-drug
conjugates,
antibody-oligonucleotide
antibody-enzyme
etc.)
work
therapeutic
applications,
special
attention
has
paid
chemistry
tools
helped
optimize
the
outcome
(i.e.,
enhanced
efficacy
reduced
side
effects)
facilitate
multifunctionalization
antibodies,
focus
on
emerging
fields
such
targeted
protein
degradation,
real-time
live-cell
imaging,
catalytic
labeling
decaging
spatiotemporal
control
well
engagement
inside
cells.
With
advances
modern
biotechnology,
well-designed
derivatives
via
size
miniaturization
together
efficient
delivery
systems
emerged,
which
gradually
improved
our
understanding
important
paved
way
pursue
novel
for
potential
treatments
diseases.
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.
Trends in Biochemical Sciences,
Год журнала:
2023,
Номер
48(5), С. 477 - 490
Опубликована: Фев. 6, 2023
Intrinsically
disordered
regions
(IDRs)
are
especially
enriched
among
proteins
that
regulate
chromatin
and
transcription.
As
a
result,
mechanisms
influence
specificity
of
IDR-driven
interactions
have
emerged
as
exciting
unresolved
issues
for
understanding
gene
regulation.
We
review
the
molecular
elements
frequently
found
within
IDRs
confer
regulatory
specificity.
In
particular,
we
summarize
differing
roles
low-complexity
(LCRs)
short
linear
motifs
(SLiMs)
towards
selective
nuclear
Examination
highlights
SLiMs
organizers
selectivity,
with
widespread
in
regulation
integration
cellular
signals.
Analysis
recurrent
between
folded
domains
suggests
diverse
avenues
to
phase-separated
condensates
opportunities
manipulate
these
control
biological
activity.
Journal of Clinical Investigation,
Год журнала:
2024,
Номер
134(1)
Опубликована: Янв. 1, 2024
The
concept
of
induced
protein
degradation
by
small
molecules
has
emerged
as
a
promising
therapeutic
strategy
that
is
particularly
effective
in
targeting
proteins
previously
considered
"undruggable."
Thalidomide
analogs,
employed
the
treatment
multiple
myeloma,
stand
prime
examples.
These
compounds
serve
molecular
glues,
redirecting
CRBN
E3
ubiquitin
ligase
to
degrade
myeloma-dependency
factors,
IKZF1
and
IKZF3.
clinical
success
thalidomide
analogs
demonstrates
potential
degradation.
Beyond
glue
degraders,
several
additional
modalities
trigger
have
been
developed
are
currently
under
evaluation.
include
heterobifunctional
polymerization-induced
degradation,
ligand-dependent
nuclear
hormone
receptors,
disruption
interactions,
various
other
strategies.
In
this
Review,
we
will
provide
concise
overview
modalities,
their
applications,
future
directions
field
Molecular Cancer Therapeutics,
Год журнала:
2024,
Номер
23(4), С. 454 - 463
Опубликована: Янв. 10, 2024
Abstract
Proteolysis
targeting
chimeras
(PROTAC)
are
an
emerging
precision
medicine
strategy,
which
targets
key
proteins
for
proteolytic
degradation
to
ultimately
induce
cancer
cell
killing.
These
hetero-bifunctional
molecules
hijack
the
ubiquitin
proteasome
system
selectively
add
polyubiquitin
chains
onto
a
specific
protein
target
degradation.
Importantly,
PROTACs
have
capacity
virtually
any
intracellular
and
transmembrane
degradation,
including
oncoproteins
previously
considered
undruggable,
strategically
positions
at
crossroads
of
multiple
research
areas.
In
this
review,
we
present
normal
functions
regulation
describe
application
improve
efficacy
current
broad-spectrum
therapeutics.
We
subsequently
potential
exploit
vulnerabilities
through
synthetic
genetic
approaches,
may
expedite
development,
translation,
utility
novel
therapies
in
cancer.
Finally,
challenges
associated
with
ongoing
efforts
overcome
these
issues
streamline
clinical
translation.
Ultimately,
lead
their
routine
use,
is
expected
revolutionize
treatment
strategies,
delay
familial
onset,
lives
outcomes
those
living
