Chemical Society Reviews,
Год журнала:
2024,
Номер
53(19), С. 9582 - 9608
Опубликована: Янв. 1, 2024
Targeted
protein
degradation
(TPD)
has
emerged
as
a
revolutionary
paradigm
in
drug
discovery
and
development,
offering
promising
avenue
to
tackle
challenging
therapeutic
targets.
Unlike
traditional
approaches
that
focus
on
inhibiting
function,
TPD
aims
eliminate
proteins
of
interest
(POIs)
using
modular
chimeric
structures.
This
is
achieved
through
the
utilization
proteolysis-targeting
chimeras
(PROTACs),
which
redirect
POIs
E3
ubiquitin
ligases,
rendering
them
for
by
cellular
ubiquitin-proteasome
system
(UPS).
Additionally,
other
technologies
such
lysosome-targeting
(LYTACs)
autophagy-based
degraders
facilitate
transportation
endo-lysosomal
or
autophagy-lysosomal
pathways
degradation,
respectively.
Despite
significant
growth
preclinical
research,
many
fail
progress
beyond
this
stage
development.
Various
factors
contribute
limited
success
agents,
including
hurdle
inadequate
delivery
target
site.
Integrating
into
platforms
could
surmount
challenges
Journal of the American Chemical Society,
Год журнала:
2023,
Номер
145(27), С. 14932 - 14944
Опубликована: Июнь 26, 2023
With
advances
in
chemically
induced
proximity
technologies,
heterobifunctional
modalities
such
as
proteolysis
targeting
chimeras
(PROTACs)
have
been
successfully
advanced
to
clinics
for
treating
cancer.
However,
pharmacologic
activation
of
tumor-suppressor
proteins
cancer
treatment
remains
a
major
challenge.
Here,
we
present
novel
Acetylation
Targeting
Chimera
(AceTAC)
strategy
acetylate
the
p53
tumor
suppressor
protein.
We
discovered
and
characterized
first
p53Y220C
AceTAC,
MS78,
which
recruits
histone
acetyltransferase
p300/CBP
mutant.
MS78
effectively
acetylated
lysine
382
(K382)
concentration-,
time-,
p300-dependent
manner
suppressed
proliferation
clonogenicity
cells
harboring
mutation
with
little
toxicity
wild-type
p53.
RNA-seq
studies
revealed
p53Y220C-dependent
upregulation
TRAIL
apoptotic
genes
downregulation
DNA
damage
response
pathways
upon
acetylation
by
MS78.
Altogether,
AceTAC
could
provide
generalizable
platform
proteins,
suppressors,
via
acetylation.
Proteolysis
targeting
chimera
(PROTAC)
technology
has
become
a
powerful
strategy
in
drug
discovery,
especially
for
undruggable
targets/proteins.
A
typical
PROTAC
degrader
consists
of
three
components:
small
molecule
that
binds
to
target
protein,
an
E3
ligase
ligand
(consisting
and
its
recruiter),
chemical
linker
hooks
first
two
components
together.
In
the
past
20
years,
we
have
witnessed
advancement
multiple
degraders
into
clinical
trials
anticancer
therapies.
However,
one
major
challenges
is
only
very
limited
number
recruiters
are
currently
available
as
targeted
protein
degradation
(TPD),
although
human
genome
encodes
more
than
600
ligases.
Thus,
there
urgent
need
identify
additional
effective
TPD
applications.
this
review,
summarized
existing
RING-type
ubiquitin
their
act
ligands
application
discovery.
We
believe
review
could
serve
reference
future
development
efficient
cancer
discovery
development.
Journal of Cellular Physiology,
Год журнала:
2024,
Номер
239(5)
Опубликована: Март 19, 2024
Abstract
Proteolysis
Targeting
Chimeras
(PROTACs)
represent
a
significant
advancement
in
therapeutic
drug
development
by
leveraging
the
ubiquitin‐proteasome
system
to
enable
targeted
protein
degradation,
particularly
impacting
oncology.
This
review
delves
into
various
types
of
PROTACs,
such
as
peptide‐based,
nucleic
acid‐based,
and
small
molecule
each
addressing
distinct
challenges
degradation.
It
also
discusses
innovative
strategies
like
bridged
PROTACs
conditional
switch‐activated
offering
precise
targeting
previously
“undruggable”
proteins.
The
potential
extends
beyond
oncology,
with
ongoing
research
technological
advancements
needed
maximize
their
potential.
Future
progress
this
field
relies
on
interdisciplinary
collaboration
integration
advanced
computational
tools
open
new
treatment
avenues
across
diseases.
Abstract
Targeting
“undruggable”
targets
with
intrinsically
disordered
structures
is
of
great
significance
for
the
treatment
disease.
The
transcription
factor
c‐Myc
controls
global
gene
expression
and
an
attractive
therapeutic
target
multiple
types
cancers.
However,
due
to
lack
defined
ligand
binding
pockets,
targeted
have
thus
far
been
unsuccessful.
Herein,
address
dilemma
lacking
ligands,
efficient
high
throughput
aptamer
screening
strategy
established,
named
polystyrene
microwell
plate‐based
systematic
evolution
ligands
by
exponential
enrichment
(microwell‐SELEX),
identify
specific
(MA9C1)
against
c‐Myc.
multifunctional
aptamer‐based
Proteolysis
Chimeras
(PROTAC)
proteolysis
(ProMyc)
developed
using
MA9C1
as
ligand.
ProMyc
not
only
significantly
degrades
ubiquitin‐proteasome
system,
but
also
reduces
Max
protein,
synergistically
inhibiting
transcriptional
activity.
Combination
artificial
cyclization
anti‐PD‐L1
(PA1)‐based
delivery
circular
PA1‐ProMyc
chimeras
achieve
tumor
regression
in
xenograft
model,
laying
a
solid
foundation
development
efficacious
degrader
clinic.
Therefore,
this
provides
invaluable
potential
drug
discovery
anti‐tumor
therapy,
offering
promising
overcome
challenge
targeting
intractable
targets.
Food Science & Nutrition,
Год журнала:
2025,
Номер
13(2)
Опубликована: Фев. 1, 2025
ABSTRACT
Proteolysis
Targeting
Chimeras
(PROTACs)
have
revolutionized
cancer
therapy
by
offering
a
selective
and
innovative
approach
to
degrade
key
oncogenic
proteins
associated
with
various
malignancies.
These
hybrid
molecules
exploit
the
ubiquitin‐proteasome
system,
facilitating
degradation
of
target
through
an
event‐driven
mechanism,
thereby
overcoming
drug
resistance
enhancing
selectivity.
With
diverse
targets
including
androgen
receptors,
BTK,
estrogen
BET
proteins,
BRAF,
PROTACs
offer
versatile
strategy
for
personalized
treatment.
Advantages
over
traditional
small
molecule
inhibitors
include
their
ability
operate
at
lower
concentrations,
catalyzing
multiple
interest
reduced
cytotoxicity.
Notably,
address
challenges
traditionally
“undruggable”
targets,
expanding
therapeutic
landscape
therapy.
Ongoing
preclinical
clinical
studies
highlight
transformative
potential
PROTACs,
promising
results
in
prostate,
breast,
lung,
melanoma,
colorectal
cancers.
Despite
potential,
persist
optimizing
physicochemical
properties
bioavailability.
Further
research
is
needed
refine
PROTAC
design
complexities
development.
Nevertheless,
development
oral
receptor
represents
significant
milestone,
demonstrating
feasibility
efficacy
this
approach.
This
review
provides
comprehensive
overview
therapy,
emphasizing
mechanism
action,
advantages,
challenges.
As
progresses,
continued
exploration
both
settings
will
be
crucial
unlocking
full
shaping
future
Journal of Translational Medicine,
Год журнала:
2025,
Номер
23(1)
Опубликована: Март 25, 2025
Metabolic
dysfunction-associated
steatotic
liver
disease
(MASLD)
is
the
most
common
chronic
worldwide,
with
a
prevalence
as
high
32.4%.
MASLD
encompasses
spectrum
of
pathologies,
ranging
from
steatosis
to
metabolic
steatohepatitis
(MASH),
fibrosis,
and,
in
some
cases,
progression
end-stage
(cirrhosis
and
hepatocellular
carcinoma).
A
comprehensive
understanding
pathogenesis
this
highly
prevalent
may
facilitate
identification
novel
targets
for
development
improved
therapies.
E3
ubiquitin
ligases
deubiquitinases
(DUBs)
are
key
regulatory
components
ubiquitin‒proteasome
system
(UPS),
which
plays
pivotal
role
maintaining
intracellular
protein
homeostasis.
Emerging
evidence
implicates
that
aberrant
expression
DUBs
involved
MASLD.
Here,
we
review
abnormalities
by
(1)
discussing
their
targets,
mechanisms,
functions
MASLD;
(2)
summarizing
pharmacological
interventions
targeting
these
enzymes
preclinical
clinical
studies;
(3)
addressing
challenges
future
therapeutic
strategies.
This
synthesizes
current
highlight
strategies
based
on
UPS
progressive
disease.
Journal of Medicinal Chemistry,
Год журнала:
2023,
Номер
66(7), С. 4932 - 4951
Опубликована: Март 17, 2023
The
CDK8–cyclin
C
complex
is
an
important
anti-tumor
target,
but
unlike
CDK8,
cyclin
remains
undruggable.
Modulators
regulating
activity
directly
are
still
under
development.
Here,
a
series
of
hydrophobic
tagging-based
degraders
the
were
designed,
synthesized,
and
evaluated
to
identify
first
dual
degrader,
LL-K8-22,
which
induced
selective
synchronous
degradation
CDK8
C.
Proteomic
immunoblot
studies
exhibited
that
LL-K8-22
significantly
degraded
without
reducing
CDK19
did
not
degrade
other
proteins
except
Moreover,
showed
enhanced
anti-proliferative
effects
over
its
parental
molecule,
BI-1347,
with
potency
increased
by
5-fold
in
MDA-MB-468
cells.
more
pronounced
on
downstream
signaling
than
suppressing
STAT1
phosphorylation
persistently.
RNA-sequencing
analysis
revealed
inhibited
E2F-
MYC-driven
carcinogenic
transcriptional
programs.
Overall,
first-in-class
degrader
would
be
useful
for
studying
unknown
functions
