Macromolecular Rapid Communications,
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 4, 2025
Targeted
protein
degradation
(TPD)
using
the
proteolysis-targeting
chimeras
(PROTACs)
is
emerging
as
a
revolutionary
technology,
offering
potential
strategy
for
cancer
treatment
by
inducing
of
overexpressed
oncogenic
proteins
in
tumors.
PROTACs
function
recruiting
E3
ligases
and
utilizing
ubiquitin-proteasome
pathway
(UPS)
to
catalyze
target
proteins.
Compared
traditional
small
molecules
inhibitors,
exhibit
enhanced
selectivity,
ability
overcome
drug
resistance,
traditionally
deemed
"undruggable".
However,
poor
water
solubility
low
cellular
permeability
significantly
limit
their
pharmacokinetic
properties,
while
systemic
toxicity
may
hinder
clinical
application.
To
address
these
limitations,
strategies
that
integrate
with
delivery
systems
are
gaining
attention.
This
review
summarizes
latest
advancements
various
enhance
vivo
efficacy
reduce
off-target
effects
PROTACs,
including
prototype
nanoparticles,
covalent
modification-based
prodrug
strategies,
innovative
multi-headed
designs,
microneedle
systems,
discussing
design
principles
associated
challenges.
The
combination
potent
multifunctional
holds
promise
accelerating
translation
improving
therapeutic
treatment.
Nature Communications,
Journal Year:
2023,
Volume and Issue:
14(1)
Published: Oct. 16, 2023
Abstract
Proteolysis-targeting
chimera
(PROTAC)
and
other
targeted
protein
degradation
(TPD)
molecules
that
induce
by
the
ubiquitin-proteasome
system
(UPS)
offer
new
opportunities
to
engage
targets
remain
challenging
be
inhibited
conventional
small
molecules.
One
fundamental
element
in
process
is
E3
ligase.
However,
less
than
2%
amongst
hundreds
of
ligases
human
genome
have
been
engaged
current
studies
TPD
field,
calling
for
recruiting
additional
ones
further
enhance
therapeutic
potential
TPD.
To
accelerate
development
PROTACs
utilizing
under-explored
ligases,
we
systematically
characterize
from
seven
different
aspects,
including
chemical
ligandability,
expression
patterns,
protein-protein
interactions
(PPI),
structure
availability,
functional
essentiality,
cellular
location,
PPI
interface
analyzing
30
large-scale
data
sets.
Our
analysis
uncovers
several
as
promising
extant
PROTACs.
In
total,
combining
confidence
score,
pattern,
PPI,
identified
76
PROTAC-interacting
candidates.
We
develop
a
user-friendly
flexible
web
portal
(
https://hanlaboratory.com/E3Atlas/
)
aimed
at
assisting
researchers
rapidly
identify
with
activities
against
specifically
desired
targets,
facilitating
these
therapies
cancer
beyond.
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.
Advanced Science,
Journal Year:
2024,
Volume and Issue:
11(25)
Published: April 19, 2024
Abstract
Proteolysis‐targeting
chimeras
(PROTACs)
have
emerged
as
a
promising
strategy
for
targeted
protein
degradation
and
drug
discovery.
To
overcome
the
inherent
limitations
of
conventional
PROTACs,
an
innovative
drugtamer‐PROTAC
conjugation
approach
is
developed
to
enhance
tumor
targeting
antitumor
potency.
Specifically,
smart
prodrug
designed
by
conjugating
“drugtamer”
nicotinamide
phosphoribosyltransferase
(NAMPT)
PROTAC
using
microenvironment
responsible
linker.
The
consists
fluorouridine
nucleotide
DNA‐like
oligomer.
Compared
NAMPT
combination
+
fluorouracil,
AS‐2F‐NP
demonstrates
superior
targeting,
efficient
cellular
uptake,
improved
in
vivo
potency
reduced
side
effects.
This
study
provides
precise
delivery
synergistic
agents.
Cancers,
Journal Year:
2024,
Volume and Issue:
16(3), P. 663 - 663
Published: Feb. 4, 2024
Induced
protein
degradation
has
emerged
as
an
innovative
drug
discovery
approach,
complementary
to
the
classical
method
of
suppressing
function.
The
androgen
receptor
signaling
pathway
been
identified
primary
driving
force
in
development
and
progression
lethal
castration-resistant
prostate
cancer.
Since
degraders
function
differently
from
antagonists,
they
hold
promise
overcome
resistance
challenges
faced
by
current
therapeutics.
Proteolysis-targeting
chimeras
(PROTACs),
monomeric
degraders,
hydrophobic
tagging,
molecular
glues,
autophagic
have
demonstrated
their
capability
downregulating
intracellular
concentrations.
potential
these
treat
cancer
is
substantiated
advancement
six
PROTACs
two
into
phase
I
or
II
clinical
trials.
Although
chemical
structures,
vitro
vivo
data,
mechanisms
reviewed,
it
crucial
stay
updated
on
recent
advances
this
field
novel
new
strategies
continue
emerge.
This
review
thus
provides
insight
advancements
paradigm,
offering
overview
progress
made
since
2020.
Theranostics,
Journal Year:
2024,
Volume and Issue:
14(4), P. 1464 - 1499
Published: Jan. 1, 2024
Epigenetics
refers
to
the
reversible
process
through
which
changes
in
gene
expression
occur
without
changing
nucleotide
sequence
of
DNA.
The
is
currently
gaining
prominence
as
a
pivotal
objective
treatment
cancers
and
other
ailments.
Numerous
drugs
that
target
epigenetic
mechanisms
have
obtained
approval
from
Food
Drug
Administration
(FDA)
for
therapeutic
intervention
diverse
diseases;
many
drawbacks,
such
limited
applicability,
toxicity,
resistance.
Since
discovery
first
proteolysis-targeting
chimeras
(PROTACs)
2001,
studies
on
targeted
protein
degradation
(TPD)-encompassing
PROTACs,
molecular
glue
(MG),
hydrophobic
tagging
(HyT),
TAG
(dTAG),
Trim-Away,
specific
non-genetic
inhibitor
apoptosis
(IAP)-dependent
eraser
(SNIPER),
antibody-PROTACs
(Ab-PROTACs),
lysosome-based
strategies-have
achieved
remarkable
progress.
In
this
review,
we
comprehensively
highlight
small-molecule
degraders
beyond
PROTACs
could
achieve
proteins
(including
bromodomain-containing
protein-related
targets,
histone
acetylation/deacetylation-related
methylation/demethylation
related
targets)
via
proteasomal
or
lysosomal
pathways.
present
difficulties
forthcoming
prospects
domain
are
also
deliberated
upon,
may
be
valuable
medicinal
chemists
when
developing
more
potent,
selective,
drug-like
clinical
applications.
Journal of Cellular Physiology,
Journal Year:
2024,
Volume and Issue:
239(5)
Published: March 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.
