Molecular Medicine,
Год журнала:
2025,
Номер
31(1)
Опубликована: Янв. 22, 2025
Abstract
Proteins
that
bind
to
DNA/RNA
are
typically
evolutionarily
conserved
with
multiple
regulatory
functions
in
transcription
initiation,
mRNA
translation,
stability
of
RNAs,
and
RNA
splicing.
Therefore,
dysregulation
binding
proteins
such
as
purine-rich
element
protein
alpha
(PURα)
disrupts
signaling
transduction
often
leads
human
diseases
including
cancer.
PURα
was
initially
recognized
a
tumor
suppressor
acute
myeloid
leukemia
(AML)
prostate
cancer
(PC).
Most
recently,
several
studies
have
revealed
is
dysregulated
cancers,
breast
(BC)
esophageal
squamous
cell
carcinoma
(ESCC).
The
oncogenic
or
tumor-suppressive
realized
via
regulating
RNA/protein
interaction,
formation
stress
granules
(SGs),
transcriptional
regulation
oncogenes
suppressors.
Although
hardly
targeted,
novel
strategies
been
applied
identify
compounds
targeting
demonstrated
promising
anti-tumor
efficacy
the
preclinical
study.
present
review
summarizes
most
recently
discovered
critical
roles
various
types,
providing
an
overview
biomarker
therapeutic
target
potential
for
patients
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Авг. 23, 2024
Abstract
Alzheimer’s
disease
(AD)
stands
as
the
predominant
form
of
dementia,
presenting
significant
and
escalating
global
challenges.
Its
etiology
is
intricate
diverse,
stemming
from
a
combination
factors
such
aging,
genetics,
environment.
Our
current
understanding
AD
pathologies
involves
various
hypotheses,
cholinergic,
amyloid,
tau
protein,
inflammatory,
oxidative
stress,
metal
ion,
glutamate
excitotoxicity,
microbiota-gut-brain
axis,
abnormal
autophagy.
Nonetheless,
unraveling
interplay
among
these
pathological
aspects
pinpointing
primary
initiators
require
further
elucidation
validation.
In
past
decades,
most
clinical
drugs
have
been
discontinued
due
to
limited
effectiveness
or
adverse
effects.
Presently,
available
primarily
offer
symptomatic
relief
often
accompanied
by
undesirable
side
However,
recent
approvals
aducanumab
(
1
)
lecanemab
2
Food
Drug
Administration
(FDA)
present
potential
in
disrease-modifying
Nevertheless,
long-term
efficacy
safety
need
Consequently,
quest
for
safer
more
effective
persists
formidable
pressing
task.
This
review
discusses
pathogenesis,
advances
diagnostic
biomarkers,
latest
updates
trials,
emerging
technologies
drug
development.
We
highlight
progress
discovery
selective
inhibitors,
dual-target
allosteric
modulators,
covalent
proteolysis-targeting
chimeras
(PROTACs),
protein-protein
interaction
(PPI)
modulators.
goal
provide
insights
into
prospective
development
application
novel
drugs.
Cell Death and Disease,
Год журнала:
2023,
Номер
14(12)
Опубликована: Дек. 21, 2023
Abstract
Pyroptosis,
apoptosis,
and
necroptosis
are
mainly
programmed
cell
death
(PCD)
pathways
for
host
defense
homeostasis.
PANoptosis
is
a
newly
distinct
inflammatory
PCD
pathway
that
uniquely
regulated
by
multifaceted
PANoptosome
complexes
highlights
significant
crosstalk
coordination
among
pyroptosis
(P),
apoptosis
(A),
and/or
necroptosis(N).
Although
some
studies
have
focused
on
the
possible
role
of
PANpoptosis
in
diseases,
pathogenesis
complex
underestimated.
Furthermore,
progress
related
agonists
or
inhibitors
disorders
has
not
yet
been
thoroughly
discussed.
In
this
perspective,
we
provide
perspectives
context
diverse
pathological
conditions
human
diseases.
The
treatment
targeting
also
summarized.
conclusion,
involved
plenty
including
but
limited
to
microbial
infections,
cancers,
acute
lung
injury/acute
respiratory
distress
syndrome
(ALI/ARDS),
ischemia-reperfusion,
organic
failure.
seems
be
double-edged
sword
conditions,
as
induces
negative
impact
prognosis
like
COVID-19
ALI/ARDS,
while
provides
protection
from
HSV1
Francisella
novicida
infection,
kills
cancer
cells
suppresses
tumor
growth
colorectal
cancer,
adrenocortical
carcinoma,
other
cancers.
Compounds
endogenous
molecules
promising
therapeutic
strategies,
which
can
act
PANoptosomes-associated
members
regulate
PANoptosis.
More
researches
needed
better
understand
pathology
develop
treatment.
Science Bulletin,
Год журнала:
2024,
Номер
69(11), С. 1776 - 1797
Опубликована: Март 29, 2024
Undruggable
targets
typically
refer
to
a
class
of
therapeutic
that
are
difficult
target
through
conventional
methods
or
have
not
yet
been
targeted,
but
great
clinical
significance.
According
statistics,
over
80%
disease-related
pathogenic
proteins
cannot
be
targeted
by
current
treatment
methods.
In
recent
years,
with
the
advancement
basic
research
and
new
technologies,
development
various
technologies
mechanisms
has
brought
perspectives
overcome
challenging
drug
targets.
Among
them,
protein
degradation
technology
is
breakthrough
strategy
for
This
can
specifically
identify
directly
degrade
utilizing
inherent
pathways
within
cells.
form
includes
types
such
as
proteolysis
targeting
chimera
(PROTAC),
molecular
glue,
lysosome-targeting
Chimaera
(LYTAC),
autophagosome-tethering
compound
(ATTEC),
autophagy-targeting
(AUTAC),
(AUTOTAC),
degrader-antibody
conjugate
(DAC).
article
systematically
summarizes
application
in
degraders
Finally,
looks
forward
future
direction
prospects
technology.
Journal of Hematology & Oncology,
Год журнала:
2025,
Номер
18(1)
Опубликована: Янв. 13, 2025
The
tumor
microenvironment
(TME)
is
integral
to
cancer
progression,
impacting
metastasis
and
treatment
response.
It
consists
of
diverse
cell
types,
extracellular
matrix
components,
signaling
molecules
that
interact
promote
growth
therapeutic
resistance.
Elucidating
the
intricate
interactions
between
cells
TME
crucial
in
understanding
progression
challenges.
A
critical
process
induced
by
epithelial-mesenchymal
transition
(EMT),
wherein
epithelial
acquire
mesenchymal
traits,
which
enhance
their
motility
invasiveness
progression.
By
targeting
various
components
TME,
novel
investigational
strategies
aim
disrupt
TME's
contribution
EMT,
thereby
improving
efficacy,
addressing
resistance,
offering
a
nuanced
approach
therapy.
This
review
scrutinizes
key
players
emphasizing
avenues
therapeutically
components.
Moreover,
article
discusses
implications
for
resistance
mechanisms
highlights
current
toward
modulation
along
with
potential
caveats.
Designing
binders
to
target
undruggable
proteins
presents
a
formidable
challenge
in
drug
discovery.
In
this
work,
we
provide
an
algorithmic
framework
design
short,
target-binding
linear
peptides,
requiring
only
the
amino
acid
sequence
of
protein.
To
do
this,
propose
process
generate
naturalistic
peptide
candidates
through
Gaussian
perturbation
peptidic
latent
space
ESM-2
protein
language
model
and
subsequently
screen
these
novel
sequences
for
target-selective
interaction
activity
via
contrastive
language-image
pretraining
(CLIP)–based
learning
architecture.
By
integrating
generative
discriminative
steps,
create
Peptide
Prioritization
CLIP
(PepPrCLIP)
pipeline
validate
highly
ranked,
target-specific
peptides
experimentally,
both
as
inhibitory
fusions
E3
ubiquitin
ligase
domains.
PepPrCLIP-derived
constructs
demonstrate
functionally
potent
binding
degradation
conformationally
diverse,
disease-driving
targets
vitro.
total,
PepPrCLIP
empowers
modulation
previously
inaccessible
without
reliance
on
stable
ordered
tertiary
structures.
Proteolysis-targeting
chimeras
(PROTACs)
represent
a
transformative
advancement
in
drug
discovery,
offering
method
to
degrade
specific
intracellular
proteins.
Unlike
traditional
inhibitors,
PROTACs
are
bifunctional
molecules
that
target
proteins
for
elimination,
enabling
the
potential
treatment
of
previously
"undruggable"
This
concept,
pioneered
by
Crews
and
his
team,
introduced
use
small
link
protein
an
E3
ubiquitin
ligase,
inducing
ubiquitination
subsequent
degradation
protein.
By
promoting
rather
than
merely
inhibiting
function,
present
novel
therapeutic
strategy
with
enhanced
specificity
effectiveness,
especially
areas
such
as
cancer
neurodegenerative
diseases.
Since
their
initial
field
PROTAC
research
has
rapidly
expanded
numerous
now
designed
wide
range
disease-relevant
The
substantial
research,
investment,
collaboration
across
academia
pharmaceutical
industry
reflect
growing
interest
PROTACs.
Review
discusses
journey
from
discovery
clinical
trials,
highlighting
advancements
challenges.
Additionally,
recent
developments
fluorescent
photogenic
PROTACs,
used
real-time
tracking
degradation,
presented,
showcasing
evolving
targeted
therapy.
Communications Chemistry,
Год журнала:
2025,
Номер
8(1)
Опубликована: Янв. 6, 2025
Abstract
Nuclear
factor
(erythroid-derived
2)-like
2
(Nrf2)
is
a
key
regulator
of
cell
detoxification,
which
maintains
homoeostasis
in
healthy
cells
and
promotes
chemoresistance
cancer
cells.
Controlling
the
expression
this
transcription
therefore
great
interest.
There
are
many
compounds
that
have
been
shown
to
induce
Nrf2
expression,
but
ligands
can
inhibit
scant.
Herein
we
characterise
an
i-motif-forming
sequence
downstream
promoter,
hypothesised
may
regulate
gene.
The
i-motif
was
found
be
stable
at
near-physiological
conditions.
We
identified
small
molecule
interact
with
structure
one
significantly
upregulated
mRNA
ligand
reduced
human
This
first
example
controlling
promoter
by
targeting
DNA
structures
offers
alternative
mode
action
for
development
improve
chemotherapeutic
responsiveness
existing
treatments
cancer.
Chemical Reviews,
Год журнала:
2024,
Номер
124(16), С. 9580 - 9608
Опубликована: Июль 2, 2024
Over
20
years
ago,
the
pyrrolysine
encoding
translation
system
was
discovered
in
specific
archaea.
Our
Review
provides
an
overview
of
how
once
obscure
pyrrolysyl-tRNA
synthetase
(PylRS)
tRNA
pair,
originally
responsible
for
accurately
translating
enzymes
crucial
methanogenic
metabolic
pathways,
laid
foundation
burgeoning
field
genetic
code
expansion.
primary
focus
is
discussion
to
successfully
engineer
PylRS
recognize
new
substrates
and
exhibit
higher
