Chemical Reviews,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 18, 2024
Molecules
that
are
able
to
induce
proximity
between
two
proteins
finding
ever
increasing
applications
in
chemical
biology
and
drug
discovery.
The
ability
introduce
an
electrophile
make
such
inducers
covalent
can
offer
improved
properties
as
selectivity,
potency,
duration
of
action,
reduced
molecular
size.
This
concept
has
been
heavily
explored
the
context
targeted
degradation
particular
for
bivalent
molecules,
but
recently,
additional
reported
other
contexts,
well
monovalent
glues.
is
a
comprehensive
review
inducers,
aiming
identify
common
trends
current
gaps
their
discovery
application.
Chemical Reviews,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 7, 2025
The
term
"undruggable"
refers
to
proteins
or
other
biological
targets
that
have
been
historically
challenging
target
with
conventional
drugs
therapeutic
strategies
because
of
their
structural,
functional,
dynamic
properties.
Drugging
such
undruggable
is
essential
develop
new
therapies
for
diseases
where
current
treatment
options
are
limited
nonexistent.
Thus,
investigating
methods
achieve
drugging
an
important
challenge
in
medicinal
chemistry.
Among
the
numerous
methodologies
drug
discovery,
covalent
modification
has
emerged
as
a
transformative
strategy.
attachment
diverse
functional
molecules
provides
powerful
platform
creating
highly
potent
and
chemical
tools
well
ability
provide
valuable
information
on
structures
dynamics
targets.
In
this
review,
we
summarize
recent
examples
biomolecules
development
therapeutics
overcome
discovery
challenges
highlight
how
contribute
toward
particular,
focus
use
chemistry
drugs,
identification,
screening,
artificial
modulation
post-translational
modifications,
cancer
specific
chemotherapies,
nucleic
acid-based
therapeutics.
Medicinal Research Reviews,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 21, 2025
ABSTRACT
Targeted
protein
degradation
(TPD)
has
emerged
as
a
significant
therapeutic
approach
for
variety
of
diseases,
including
cancer.
Advances
in
TPD
techniques,
such
molecular
glue
(MG)
and
lysosome‐dependent
strategies,
have
shown
substantial
progress
since
the
inception
first
PROTAC
2001.
The
methodology
represents
forefront
technology,
with
ongoing
evaluation
more
than
20
clinical
trials
treatment
diverse
medical
conditions.
Two
prominent
PROTACs,
ARV‐471
ARV‐110,
are
currently
undergoing
phase
III
II
trials,
respectively.
Traditional
PROTACs
encountering
obstacles
limited
binding
affinity
restricted
range
E3
ligase
ligands
facilitating
interest
(POI)
degradation.
Covalent
medicines
offer
potential
to
enhance
efficacy
by
enabling
targeting
previously
considered
“undruggable”
shallow
sites.
Strategic
alterations
allow
establish
covalent
connections
particular
target
proteins,
Kirsten
rat
sarcoma
viral
oncogene
homolog
(KRAS),
Bruton's
tyrosine
kinase
(BTK),
epidermal
growth
factor
receptor
(EGFR),
well
ligases
DDB1
CUL4
associated
16
(DCAF16)
Kelch‐like
ECH‐associated
1
(Keap1).
concept
also
been
utilized
various
new
forms
degraders,
molecule
(MG),
in‐cell
click‐formed
proteolysis
chimera
(CLIPTAC),
HaloPROTAC,
lysosome‐targeting
(LYTAC)
GlueTAC.
This
review
focuses
on
recent
advancements
degraders
beyond
examines
future
directions
pertinent
this
field.
Journal of Medicinal Chemistry,
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 6, 2025
Given
the
critical
role
of
STING
in
autoimmune
and
inflammatory
disorders,
development
targeted
small-molecule
inhibitors
has
been
a
promising
strategy
for
treatment
these
diseases.
Nevertheless,
currently
reported
suffer
from
limited
structural
diversity,
species
sensitivity,
poor
activity;
therefore,
none
are
suitable
clinical
investigation.
Herein,
we
performed
modification
campaign
on
tool
compound
6
(H-151)
based
its
potential
metabolic
hotspots.
Compound
66,
bearing
difluorobenzodioxol
moiety,
was
identified
as
one
most
potent
with
IC50
values
116
96.3
nM
h-
m-STING,
respectively.
This
exhibited
notable
enhancement
properties,
especially
terms
stability.
A
mechanism
study
verified
that
66
engaged
covalent
manner
akin
to
6.
In
both
cisplatin-induced
acute
kidney
injury
TREX1
D18N
mouse
models,
significantly
alleviated
tissue
inflammation.
Expert Opinion on Drug Discovery,
Journal Year:
2025,
Volume and Issue:
unknown
Published: May 24, 2025
Pyridones
are
six-membered,
nitrogen-containing
heterocycles,
possessing
two
isomeric
forms;
these
2-pyridones
and
4-pyridones.
Both
pyridone
rings
display
unique
physicochemical
properties
including
weak
alkalinity
dual
hydrogen-bond
donor/acceptor
propensities.
These
heterocyclic
compounds
particularly
underlined
for
their
diverse
biological
effects,
cytotoxicity
activity
as
well
antibacterial,
antiviral,
anti-inflammatory,
anti-fibrotic
properties.
This
versatility
has
attracted
remarkable
interest
held
promise
addressing
the
challenges
of
drug
resistance.
review
is
outcome
literature
searches
conducted
on
articles
published
between
2022
2025
across
several
major
databases,
PubMed,
Scopus,
Web
Science,
using
specific
keywords
concerning
'pyridone'
'bioactivity.'
It
focuses
identification
therapeutic
targets,
process
molecular
mechanisms,
plausible
modes
interaction
binding.
have
been
reported
to
exhibit
a
wide
range
bioactivities
by
regulating
critical
signaling
pathways
that
influence
downstream
gene
expression,
intracellular
enzyme
cytoskeletal
configuration.
They
consequently
used
privileged
fragments
in
design
biologically
active
molecules
with
promising
application
value
pharmaceutical
chemistry.
Further
investigation
will
be
required
enhance
drug-like
Continuous
progress
structure
optimization
clinical
trial
results
help
provide
guideline
future
candidate
discovery.
