Abstract
Chemically
induced
proximity
(CIP)
refers
to
co‐opting
naturally
occurring
biological
pathways
using
synthetic
molecules
recruit
neosubstrates
that
are
not
normally
encountered
or
enhance
the
affinity
of
interactions.
Leveraging
biology
through
CIPs
has
become
a
rapidly
evolving
field
and
garnered
considerable
interest
in
basic
research
drug
discovery.
PROteolysis
TArgeting
Chimera
(PROTAC)
is
well‐established
CIP
modality
induces
between
target
protein
an
E3
ubiquitin
ligase,
causing
degradation
via
ubiquitin‐proteasome
system.
Inspired
by
PROTACs,
several
other
modalities
have
emerged
modulate
both
proteins
RNA
over
recent
years.
In
this
review,
we
summarize
critical
advances
opportunities
field,
focusing
on
degraders,
degraders
non‐degrader
such
as
post‐translational
modification
(PTM)
protein‐protein
interaction
(PPI)
modulators.
We
envision
these
emerging
proximity‐based
will
be
valuable
resources
for
therapeutic
discovery
future.
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(10), С. 5489 - 5489
Опубликована: Май 17, 2024
Over
120
small-molecule
kinase
inhibitors
(SMKIs)
have
been
approved
worldwide
for
treating
various
diseases,
with
nearly
70
FDA
approvals
specifically
cancer
treatment,
focusing
on
targets
like
the
epidermal
growth
factor
receptor
(EGFR)
family.
Kinase-targeted
strategies
encompass
monoclonal
antibodies
and
their
derivatives,
such
as
nanobodies
peptides,
along
innovative
approaches
use
of
degraders
protein
interaction
inhibitors,
which
recently
demonstrated
clinical
progress
potential
in
overcoming
resistance.
Nevertheless,
kinase-targeted
encounter
significant
hurdles,
including
drug
resistance,
greatly
impacts
benefits
patients,
well
concerning
toxicity
when
combined
immunotherapy,
restricts
full
utilization
current
treatment
modalities.
Despite
these
challenges,
development
remains
highly
promising.
The
extensively
studied
tyrosine
family
has
70%
its
stages
development,
while
30%
inadequately
explored.
Computational
technologies
play
a
vital
role
accelerating
novel
repurposing
existing
drugs.
Recent
FDA-approved
SMKIs
underscore
importance
blood-brain
barrier
permeability
long-term
patient
benefits.
This
review
provides
comprehensive
summary
recent
based
mechanisms
action
targets.
We
summarize
latest
developments
new
explore
emerging
inhibition
from
perspective.
Lastly,
we
outline
obstacles
future
prospects
inhibition.
Drug
resistance
in
cancer
cells
significantly
diminishes
treatment
efficacy,
leading
to
recurrence
and
metastasis.
A
critical
factor
contributing
this
is
the
epigenetic
alteration
of
gene
expression
via
RNA
modifications,
such
as
N6-methyladenosine
(m6A),
N1-methyladenosine
(m1A),
5-methylcytosine
(m5C),
7-methylguanosine
(m7G),
pseudouridine
(Ψ),
adenosine-to-inosine
(A-to-I)
editing.
These
modifications
are
pivotal
regulating
splicing,
translation,
transport,
degradation,
stability.
Governed
by
"writers,"
"readers,"
"erasers,"
impact
numerous
biological
processes
progression,
including
cell
proliferation,
stemness,
autophagy,
invasion,
apoptosis.
Aberrant
can
lead
drug
adverse
outcomes
various
cancers.
Thus,
targeting
modification
regulators
offers
a
promising
strategy
for
overcoming
enhancing
efficacy.
This
review
consolidates
recent
research
on
role
prevalent
resistance,
with
focus
m6A,
m1A,
m5C,
m7G,
Ψ,
A-to-I
Additionally,
it
examines
regulatory
mechanisms
linked
underscores
existing
limitations
field.
ACS Pharmacology & Translational Science,
Год журнала:
2025,
Номер
8(3), С. 654 - 672
Опубликована: Фев. 10, 2025
Dysregulation
of
correct
protein
tau
homeostasis
represents
the
seed
for
development
several
devastating
central
nervous
system
disorders,
known
as
tauopathies,
that
affect
millions
people
worldwide.
Despite
massive
public
and
private
support
to
research
funding,
these
diseases
still
represent
unmet
medical
needs.
In
fact,
tau-targeting
tools
developed
date
have
failed
translate
into
clinic.
Recently,
taking
advantage
modes
nature
uses
mediate
flow
information
in
cells,
researchers
a
new
class
molecules,
called
proximity-inducing
modulators,
which
exploit
spatial
proximity
modulate
function(s)
redirect
cellular
processes.
this
perspective,
after
brief
discussion
about
classic
approaches,
we
will
discuss
different
classes
modulators
so
far
highlight
applications
protein's
function
tau-induced
toxicity.
Biomolecules,
Год журнала:
2023,
Номер
13(10), С. 1555 - 1555
Опубликована: Окт. 20, 2023
The
RAS-ERK
pathway
is
a
fundamental
signaling
cascade
crucial
for
many
biological
processes
including
proliferation,
cell
cycle
control,
growth,
and
survival;
common
across
all
types.
Notably,
ERK1/2
are
implicated
in
specific
context-dependent
manner
as
stem
cells
pancreatic
β-cells.
Alterations
the
different
components
of
this
result
dysregulation
effector
kinases
which
communicate
with
hundreds
substrates.
Aberrant
activation
contributes
to
range
disorders,
cancer.
This
review
provides
an
overview
structure,
activation,
regulation,
mutational
frequency
tiers
cascade;
particular
focus
on
ERK1/2.
We
highlight
importance
scaffold
proteins
that
contribute
kinase
localization
coordinate
interaction
dynamics
substrates,
activators,
inhibitors.
Additionally,
we
explore
innovative
therapeutic
approaches
emphasizing
promising
avenues
field.
Frontiers in Immunology,
Год журнала:
2024,
Номер
15
Опубликована: Янв. 17, 2024
Despite
the
clear
benefits
demonstrated
by
immunotherapy,
there
is
still
an
inevitable
off-target
effect
resulting
in
serious
adverse
immune
reactions.
In
recent
years,
research
and
development
of
Drug
Delivery
System
(DDS)
has
received
increased
prominence.
decades
development,
DDS
ability
to
deliver
drugs
a
precisely
targeted
manner
mitigate
side
effects
advantages
flexible
control
drug
release,
improved
pharmacokinetics,
distribution.
Therefore,
we
consider
that
combining
cancer
immunotherapy
with
can
enhance
anti-tumor
ability.
this
paper,
provide
overview
latest
delivery
strategies
briefly
introduce
characteristics
based
on
nano-carriers
(liposomes,
polymer
nano-micelles,
mesoporous
silica,
extracellular
vesicles,
etc.)
coupling
technology
(ADCs,
PDCs
protein
degradation).
Our
aim
show
readers
variety
platforms
under
different
mechanisms,
analyze
their
limitations,
more
superior
accurate
targeting
for
immunotherapy.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Июль 10, 2024
Recently,
targeted
degradation
has
emerged
as
a
powerful
therapeutic
modality.
Relying
on
"event-driven"
pharmacology,
proteolysis
targeting
chimeras
(PROTACs)
can
degrade
targets
and
are
superior
to
conventional
inhibitors
against
undruggable
proteins.
Unfortunately,
PROTAC
discovery
is
limited
by
warhead
scarcity
laborious
optimization
campaigns.
To
address
these
shortcomings,
analogous
protein-based
heterobifunctional
degraders,
known
bioPROTACs,
have
been
developed.
Compared
small-molecule
PROTACs,
bioPROTACs
higher
success
rates
subject
fewer
design
constraints.
However,
the
membrane
impermeability
of
proteins
severely
restricts
bioPROTAC
deployment
generalized
Here,
we
present
an
engineered
template
able
complex
with
cationic
ionizable
lipids
via
electrostatic
interactions
for
cytosolic
delivery.
When
delivered
biocompatible
lipid
nanoparticles,
modified
rapidly
intracellular
proteins,
exhibiting
near-complete
elimination
(up
95%
clearance)
within
hours
treatment.
Our
format
localized
various
subcellular
compartments
including
mitochondria,
nucleus,
cytosol,
membrane.
Moreover,
substrate
specificity
be
easily
reprogrammed,
allowing
modular
clinically-relevant
such
Ras,
Jnk,
Erk.
In
summary,
this
work
introduces
inexpensive,
flexible,
scalable
platform
efficient
that
may
elude
chemical
inhibition.
The
authors,
actively
engaged
in
the
development
of
mesoporous
silica‐based
solutions,
initially
for
modified
drug
release,
later
smart
administration
conventional
chemotherapeutic
cytotoxic
drugs,
present
evolution
concept
targeted
therapy
across
different
disciplines.
They
also
discuss
diverse
therapeutic
needs
and
related
challenges
(adverse
effects)
that
have
unfolded
over
last
30
years.
Nanomedicine
potentialities,
mainly
against
cancers,
emerged
globally
during
intense
research
activity
few
decades,
are
critically
discussed.
authors
glimpse
growing
potential
immune‐based
including
those
assisted
by
nanotechnology,
as
well
molecular
therapies
(MTT)
on
which
they
focus.
advantages
offered
therapies,
despite
limits
monotargeted
suggest
engineering
multi‐targeted
therapies.
solutions
such
ligand‐specific
internalization
pH‐sensitive
release
extensively
tested
recently
presented
open
literature,
still
remain
available
instruments.
According
to
MTT
can
offer
shining
perspectives
near
future
will
depend
a
thorough
comprehension
nanostructures
synthesis
tumor
physiology.
This
article
gives
an
interdisciplinary
point
view
tailored
non‐specialist
readers
imagining
possible
scenarios
field.
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
