Journal of the American Chemical Society,
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 30, 2024
PROTACs
have
emerged
as
a
therapeutic
modality
for
the
targeted
degradation
of
proteins
interest
(POIs).
Central
to
PROTAC
technology
are
E3
ligase
recruiters,
yet
only
few
them
been
identified
due
lack
ligandable
pockets
in
ligases,
especially
among
single-subunit
ligases.
We
propose
that
binders
partner
ligases
could
be
repurposed
new
recruiters.
MDM2
is
overexpressed
tumors.
Nucleolin
(NCL)
an
protein
displays
similar
tumor-specific
overexpression
pattern
and
nuclear-cytoplasmic
shuttling
role
MDM2.
Furthermore,
NCL
selectively
translocated
on
tumor
cell
surface,
where
it
acts
internalization
receptor
its
binders.
reveal
NCL-binding
Oridonin
(Ori),
natural
ent-kaurene
diterpenoid,
capable
recruiting
by
employing
molecular
bridge.
design
Ori-based
modulating
oncogenic
POIs,
including
BRD4
EGFR.
These
direct
assembly
MDM2-NCL-PROTAC-POI
complexes
induce
proteasomal
POIs
shrinkage.
In
addition
engaged
PROTACs,
MDM2,
along
with
homologue
MDMX,
plays
nonredundant
function
inhibiting
p53
activity.
Dual
inhibition
MDM2/X
proposed
promising
antitumor
strategy.
demonstrate
Ori
also
recruits
MDMX
NCL-dependent
manner.
homo-PROTACs
dual
attenuate
progression.
Our
findings
prove
feasibility
repurposing
recruiters
highlight
potential
recruiter.
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.
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 9, 2024
Targeted
protein
degradation
(TPD),
including
the
use
of
proteolysis-targeting
chimeras
(PROTACs)
and
molecular
glue
degraders
(MGDs)
to
degrade
proteins,
is
an
emerging
strategy
develop
novel
therapies
for
cancer
beyond.
PROTACs
or
MGDs
function
by
inducing
proximity
between
E3
ligase
a
interest
(POI),
leading
ubiquitination
consequent
proteasomal
POI.
Notably,
one
major
issue
in
TPD
lack
ligandable
ligases,
as
current
studies
predominantly
CUL4
EBioMedicine,
Год журнала:
2024,
Номер
104, С. 105162 - 105162
Опубликована: Май 28, 2024
Finding
the
oncogene,
which
was
able
to
inhibit
tumor
cells
intrinsically
and
improve
immune
answers,
will
be
future
direction
for
renal
cancer
combined
treatment.
Following
patient
sample
analysis
signaling
pathway
examination,
we
propose
p21-activated
kinase
4
(PAK4)
as
a
potential
target
drug
kidney
cancer.
PAK4
exhibits
high
expression
levels
in
samples
plays
regulatory
role
microenvironment.
Expert Opinion on Drug Discovery,
Год журнала:
2024,
Номер
19(3), С. 267 - 280
Опубликована: Янв. 12, 2024
Introduction
The
concept
of
click
chemistry
was
introduced
in
2001
as
an
effective,
efficient,
and
sustainable
approach
to
making
functional
groups
harnessing
the
thermodynamic
properties
a
set
known
chemical
reactions
that
are
based
on
nature.
Some
most
common
examples
include
produce
1,2,3-triazoles,
which
have
been
used
with
great
success
drug
discovery
development,
biology.
unite
two
molecules
quickly
irreversibly,
can
be
performed
inside
living
cells,
without
harming
cell.
Abstract
Ubiquitinylation
of
protein
substrates
results
in
various
but
distinct
biological
consequences,
among
which
ubiquitin-mediated
degradation
is
most
well
studied
for
its
therapeutic
application.
Accordingly,
artificially
targeted
ubiquitin-dependent
proteins
has
evolved
into
the
therapeutically
relevant
PROTAC
technology.
This
tethered
ubiquitinylation
targets
coupled
with
a
broad
assortment
modifying
E3
ubiquitin
ligases
been
made
possible
by
rational
design
bi-specific
chimeric
molecules
that
bring
these
proximity.
However,
forced
inflicted
binary
warheads
molecule
should
not
necessarily
result
can
be
used
to
modulate
other
cellular
functions.
In
this
respect
it
noted
diverse
set
known
control
their
transport,
transcriptional
activity,
and
protein-protein
interactions.
review
provides
examples
potential
usage
based
on
non-degradable
ubiquitinylation.
