Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 20, 2024
Beyond
the
rapid
achievements
of
therapeutic
heterobifunctional
molecules,
some
recent
efforts
have
focused
on
constructing
heterotrifunctional
aiming
at
developing
more
potent
and
selective
agents
or
emerging
additional
functions
to
molecules.
However,
synthesis
these
complex
molecules
requires
a
specific
design
lengthy
steps.
We
developed
two-step
strategy
for
modular
construction
enabled
by
sustainable
convenient
iodosulfonylation
allenes
followed
SN2′-selective
amination.
This
successfully
incorporates
broad
range
biologically
active
labeling
them
with
fluorescent
group.
The
applications
obtained
compounds
in
protein
labeling,
subcellular
imaging,
targeted
inhibition
tumor
cells
make
this
highly
appealing.
Journal of the American Chemical Society,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 3, 2025
Proteolysis-targeting
chimeras
(PROTACs)
are
dual-functional
molecules
composed
of
a
protein
interest
(POI)
ligand
and
an
E3
ligase
connected
by
linker,
which
can
recruit
POI
ligases
simultaneously,
thereby
inducing
the
degradation
showing
great
potential
in
disease
treatment.
A
challenge
developing
PROTACs
is
design
linkers
modification
ligands
to
establish
multifunctional
platform
that
enhances
efficiency
antitumor
activity.
As
programmable
modifiable
nanomaterial,
DNA
tetrahedron
precisely
assemble
selectively
recognize
flexibly
adjust
distance
between
molecules,
making
them
ideal
linkers.
Herein,
we
developed
multivalent
PROTAC
based
on
tetrahedron,
named
AS-TD2-PRO.
Using
as
combined
modules
targeting
tumor
cells,
recognizing
ligases,
multiple
together.
We
took
undruggable
target
signal
transducer
activator
transcription
3
(STAT3),
associated
with
etiology
progression
variety
malignant
tumors,
example
this
study.
AS-TD2-PRO
two
STAT3
recognition
demonstrated
good
enhancing
tumor-specific
compared
traditional
bivalent
PROTACs.
Furthermore,
mouse
model,
superior
therapeutic
activity
was
observed.
Overall,
tetrahedron-driven
both
serve
proof
principle
for
introduce
promising
avenue
cancer
treatment
strategies.
Bioanalysis,
Год журнала:
2025,
Номер
unknown, С. 1 - 16
Опубликована: Фев. 3, 2025
Undruggable
targets
account
for
roughly
85%
of
human
disease-related
and
represent
a
category
therapeutic
that
are
difficult
to
tackle
with
traditional
methods,
but
their
considerable
clinical
importance.
These
generally
defined
by
planar
functional
interfaces
the
absence
efficient
ligand-binding
pockets,
making
them
unattainable
conventional
pharmaceutical
strategies.
The
advent
oligonucleotide-based
proteolysis-targeting
chimeras
(PROTACs)
has
instilled
renewed
optimism
in
addressing
these
challenges.
PROTACs
facilitate
targeted
degradation
undruggable
entities,
including
transcription
factors
(TFs)
RNA-binding
proteins
(RBPs),
via
proteasome-dependent
mechanisms,
thereby
presenting
novel
approaches
diseases
linked
targets.
This
review
offers
an
in-depth
examination
recent
progress
integration
PROTAC
technology
oligonucleotides
target
traditionally
proteins,
emphasizing
design
principles
mechanisms
action
innovative
PROTACs.
Frontiers in Pharmacology,
Год журнала:
2025,
Номер
16
Опубликована: Фев. 11, 2025
Drug
discovery
plays
a
crucial
role
in
medicinal
chemistry,
serving
as
the
cornerstone
for
developing
new
treatments
to
address
wide
range
of
diseases.
This
review
emphasizes
significance
advanced
strategies,
such
Click
Chemistry,
Targeted
Protein
Degradation
(TPD),
DNA-Encoded
Libraries
(DELs),
and
Computer-Aided
Design
(CADD),
boosting
drug
process.
Chemistry
streamlines
synthesis
diverse
compound
libraries,
facilitating
efficient
hit
lead
optimization.
TPD
harnesses
natural
degradation
pathways
target
previously
undruggable
proteins,
while
DELs
enable
high-throughput
screening
millions
compounds.
CADD
employs
computational
methods
refine
candidate
selection
reduce
resource
expenditure.
To
demonstrate
utility
these
methodologies,
we
highlight
exemplary
small
molecules
discovered
past
decade,
along
with
summary
marketed
drugs
investigational
that
exemplify
their
clinical
impact.
These
examples
illustrate
how
techniques
directly
contribute
advancing
chemistry
from
bench
bedside.
Looking
ahead,
Artificial
Intelligence
(AI)
technologies
interdisciplinary
collaboration
are
poised
growing
complexity
discovery.
By
fostering
deeper
understanding
transformative
this
aims
inspire
innovative
research
directions
further
advance
field
chemistry.
Bioconjugate Chemistry,
Год журнала:
2024,
Номер
35(8), С. 1089 - 1115
Опубликована: Июль 11, 2024
Targeted
protein
degradation
or
TPD,
is
rapidly
emerging
as
a
treatment
that
utilizes
small
molecules
to
degrade
proteins
cause
diseases.
TPD
allows
for
the
selective
removal
of
disease-causing
proteins,
including
proteasome-mediated
degradation,
lysosome-mediated
and
autophagy-mediated
degradation.
This
approach
has
shown
great
promise
in
preclinical
studies
now
being
translated
treat
numerous
diseases,
neurodegenerative
infectious
cancer.
review
discusses
latest
advances
its
potential
new
chemical
modality
immunotherapy,
with
special
focus
on
innovative
applications
cutting-edge
research
PROTACs
(Proteolysis
TArgeting
Chimeras)
their
efficient
translation
from
scientific
discovery
technological
achievements.
Our
also
addresses
significant
obstacles
prospects
this
domain,
while
offering
insights
into
future
immunotherapeutic
applications.
