bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Feb. 15, 2024
Abstract
Alkenyl
oxindoles
have
been
characterized
as
autophagosome-tethering
compounds
(ATTECs),
which
can
target
mutant
huntingtin
protein
(mHTT)
for
lysosomal
degradation.
In
order
to
expand
the
application
of
alkenyl
targeted
degradation,
we
designed
and
synthesized
a
series
hetero-bifunctional
by
conjugating
different
with
BRD4
inhibitor
JQ1.
Through
structure-activity
relationship
study,
successfully
developed
JQ1-alkenyl
oxindole
conjugates
that
potently
degrade
BRD4.
Unexpectedly,
found
these
molecules
through
ubiquitin-proteasome
system,
rather
than
autophagy-lysosomal
pathway.
Using
pooled
CRISPR
interference
(CRISPRi)
screening,
revealed
recruit
E3
ubiquitin
ligase
complex
CRL4
DCAF11
substrate
Furthermore,
validated
most
potent
molecule
HL435
promising
drug-like
lead
compound
exert
antitumor
activity
both
in
vitro
vivo
.
Our
research
provides
new
employable
PROTAC
moieties
providing
possibilities
drug
discovery.
Journal of Clinical Investigation,
Journal Year:
2023,
Volume and Issue:
133(18)
Published: Sept. 14, 2023
Antibody-drug
conjugates
(ADCs)
have
emerged
as
a
revolutionary
therapeutic
class,
combining
the
precise
targeting
ability
of
monoclonal
antibodies
with
potent
cytotoxic
effects
chemotherapeutics.
Notably,
ADCs
rapidly
advanced
in
field
breast
cancer
treatment.
This
innovative
approach
holds
promise
for
strengthening
immune
system
through
antibody-mediated
cellular
toxicity,
tumor-specific
immunity,
and
adaptive
responses.
However,
development
upfront
acquired
resistance
poses
substantial
challenges
maximizing
effectiveness
these
therapeutics,
necessitating
deeper
understanding
underlying
mechanisms.
These
mechanisms
include
antigen
loss,
derangements
ADC
internalization
recycling,
drug
clearance,
alterations
signaling
pathways
payload
target.
To
overcome
resistance,
ongoing
research
efforts
are
focused
on
urgently
identifying
biomarkers,
integrating
therapy
approaches,
designing
novel
payloads.
Review
provides
an
overview
clinical
ADCs,
explores
their
unique
immune-boosting
function,
while
also
highlighting
complex
safety
that
must
be
addressed.
A
continued
focus
how
impact
tumor
microenvironment
will
help
to
identify
new
payloads
can
improve
patient
outcomes.
PLoS Biology,
Journal Year:
2024,
Volume and Issue:
22(5), P. e3002550 - e3002550
Published: May 20, 2024
Alkenyl
oxindoles
have
been
characterized
as
autophagosome-tethering
compounds
(ATTECs),
which
can
target
mutant
huntingtin
protein
(mHTT)
for
lysosomal
degradation.
In
order
to
expand
the
application
of
alkenyl
targeted
degradation,
we
designed
and
synthesized
a
series
heterobifunctional
by
conjugating
different
with
bromodomain-containing
4
(BRD4)
inhibitor
JQ1.
Through
structure-activity
relationship
study,
successfully
developed
JQ1-alkenyl
oxindole
conjugates
that
potently
degrade
BRD4.
Unexpectedly,
found
these
molecules
BRD4
through
ubiquitin-proteasome
system,
rather
than
autophagy-lysosomal
pathway.
Using
pooled
CRISPR
interference
(CRISPRi)
screening,
revealed
recruit
E3
ubiquitin
ligase
complex
CRL4DCAF11
substrate
Furthermore,
validated
most
potent
molecule
HL435
promising
drug-like
lead
compound
exert
antitumor
activity
both
in
vitro
mouse
xenograft
tumor
model.
Our
research
provides
new
employable
proteolysis
targeting
chimera
(PROTAC)
moieties
providing
possibilities
drug
discovery.
Cellular Signalling,
Journal Year:
2025,
Volume and Issue:
127, P. 111606 - 111606
Published: Jan. 13, 2025
Clear
cell
renal
carcinoma
(ccRCC)
is
a
common
clinical
tumor
of
the
urinary
system.
The
lack
effective
diagnostic
and
treatment
options
poses
serious
challenge
to
treatment.
Therefore,
identifying
molecular
targets
has
become
one
potential
means
treat
this
disease.
Firstly,
analysis
TCGA
database
found
that
PLAC1
was
abnormally
highly
expressed
in
ccRCC
negatively
correlated
with
patient
prognosis.
Western
blotting
immunofluorescence
experiments
further
verified
patients,
knockdown
inhibited
development
vitro.
Last,
high-throughput
virtual
screening
technology
(HTVS)
performed
identify
two
inhibitors
，AmB
Cana,
which
were
able
reduce
expression
progression
ccRCC.
In
conclusion,
current
investigation
indicated
could
serve
as
prognostic
biomarker,
AmB
Cana
inhibit
by
reducing
PLAC1,
making
it
therapeutic
option
for
Small,
Journal Year:
2024,
Volume and Issue:
20(26)
Published: Jan. 22, 2024
The
development
of
miniaturized
high-throughput
in
situ
screening
platforms
capable
handling
the
entire
process
drug
synthesis
to
final
is
essential
for
advancing
discovery
future.
In
this
study,
an
approach
based
on
combinatorial
solid-phase
synthesis,
enabling
efficient
libraries
proteolysis
targeting
chimeras
(PROTACs)
array
format
presented.
This
on-chip
platform
allows
direct
biological
without
need
transfer
steps.
UV-induced
release
target
molecules
into
individual
droplets
facilitates
further
experimentation.
Utilizing
a
mitogen-activated
protein
kinase
kinases
(MEK1/2)
degrader
as
template,
series
132
novel
PROTAC-like
synthesized
using
Ugi
reaction.
These
compounds
are
characterized
various
methods,
including
matrix-assisted
laser
desorption
ionization
mass
spectrometry
(MALDI-MS)
imaging,
while
consuming
only
few
milligrams
starting
materials
total.
Furthermore,
feasibility
culturing
cancer
cells
modified
spots
and
quantifying
effect
MEK
suppression
demonstrated.
lays
foundation
potent
PROTACs
potential
anticancer
activity
offers
accelerating
by
integrating
steps
same
array.
