Angewandte Chemie,
Год журнала:
2023,
Номер
135(11)
Опубликована: Янв. 10, 2023
Abstract
Casein
kinases
1
(CK1)
are
key
signaling
molecules
that
have
emerged
recently
as
attractive
therapeutic
targets
in
particular
for
the
treatment
of
hematological
malignancies.
Herein,
we
report
identification
a
new
class
potent
and
highly
selective
inhibitors
CK1α,
δ
ϵ.
Based
on
their
optimal
vitro
vivo
profiles
exclusive
selectivity,
MU1250,
MU1500
MU1742
were
selected
quality
chemical
probes
those
CK1
isoforms.
At
proper
concentrations,
MU1250
allow
specific
targeting
CK1δ
or
dual
inhibition
CK1δ/ϵ
cells.
The
compound
also
efficiently
inhibits
CK1α
and,
to
our
knowledge,
represents
first
inhibitor
this
enzyme.
In
addition,
demonstrate
central
H
‐pyrrolo[2,3‐
b
]pyridine‐imidazole
pharmacophore
can
be
used
basis
other
therapeutically
relevant
protein
kinases,
e.g.
p38α,
exemplified
by
MU1299.
Nature Medicine,
Год журнала:
2022,
Номер
28(10), С. 2162 - 2170
Опубликована: Сен. 12, 2022
Abstract
Anti-BRAF/EGFR
therapy
was
recently
approved
for
the
treatment
of
metastatic
BRAF
V600E
colorectal
cancer
(mCRC
BRAF-V600E
).
However,
a
large
fraction
patients
do
not
respond,
underscoring
need
to
identify
molecular
determinants
response.
Using
whole-exome
sequencing
in
discovery
cohort
with
mCRC
treated
anti-BRAF/EGFR
therapy,
we
found
that
inactivating
mutations
RNF43
,
negative
regulator
WNT,
predict
improved
response
rates
and
survival
outcomes
microsatellite-stable
(MSS)
tumors.
Analysis
an
independent
validation
confirmed
relevance
predicting
clinical
benefit
(72.7%
versus
30.8%;
P
=
0.03),
as
well
longer
progression-free
(hazard
ratio
(HR),
0.30;
95%
confidence
interval
(CI),
0.12–0.75;
0.01)
overall
(HR,
0.26;
CI,
0.10–0.71;
0.008),
MSS-
mutated
wild-type
Microsatellite-instable
tumors
invariably
carried
wild-type-like
genotype
encoding
p.G659fs
presented
intermediate
profile.
We
no
association
patient
control
MSS-mCRC
exposed
anti-BRAF
targeted
therapies.
Overall,
our
findings
suggest
cross-talk
between
MAPK
WNT
pathways
may
modulate
antitumor
activity
uncover
predictive
biomarkers
optimize
management
these
patients.
Life Science Alliance,
Год журнала:
2024,
Номер
7(9), С. e202402575 - e202402575
Опубликована: Июль 5, 2024
The
transmembrane
E3
ligases
RNF43
and
ZNRF3
perform
key
tumour
suppressor
roles
by
inducing
endocytosis
of
members
the
Frizzled
(FZD)
family,
primary
receptors
for
WNT.
Loss-of-function
mutations
in
mediate
FZD
stabilisation
a
WNT-hypersensitive
growth
state
various
cancer
types.
Strikingly,
are
differentially
distributed
across
types,
raising
questions
about
their
functional
redundancy.
Here,
we
compare
efficacy
targeting
different
FZDs
endocytosis.
We
find
that
preferentially
down-regulates
FZD1/FZD5/FZD7,
whereas
displays
preference
towards
FZD6.
show
domain
(TMD)
is
molecular
determinant
FZD5
Furthermore,
TMD
swap
between
re-directs
down-regulation.
conclude
down-regulate
specific
FZDs,
part
TMD-dependent
mechanism.
In
accordance,
tissue-specific
expression
patterns
homologues
correlate
with
incidence
or
those
tissues.
Consequently,
our
data
point
to
druggable
vulnerabilities
-
-mutant
human
cancers.
Frontiers in Cell and Developmental Biology,
Год журнала:
2022,
Номер
10
Опубликована: Май 11, 2022
The
establishment
of
polarity
within
tissues
and
dynamic
cellular
morphogenetic
events
are
features
common
to
both
developing
adult
tissues,
breakdown
these
programs
is
associated
with
diverse
human
diseases.
Wnt/Planar
cell
(Wnt/PCP)
signaling,
a
branch
non-canonical
Wnt
critical
the
maintenance
in
epithelial
as
well
motility
proper
embryonic
development.
In
Wnt/PCP-mediated
planar
relies
upon
asymmetric
distribution
core
proteins
establish
polarity,
but
requirement
for
this
remains
unclear.
However,
polarized
migratory
cells,
Wnt/PCP-specific
transmembrane
protein
Vangl
required
appears
serve
scaffold
which
pathway
components
positive
negative
regulators
Wnt/PCP
signaling
assemble.
current
literature
suggests
that
multiple
interaction
domains
allow
binding
partners
context-
tissue-specific
complexes.
review
we
discuss
role
master
tissue
address
how
dysregulated
disease.
Pharmacology & Therapeutics,
Год журнала:
2022,
Номер
238, С. 108179 - 108179
Опубликована: Март 28, 2022
Gastrointestinal
cancers
are
responsible
for
more
cancer
deaths
than
any
other
system
of
the
body.
This
review
summarises
how
Wnt
pathway
dysregulation
contributes
to
development
most
common
gastrointestinal
cancers,
with
a
particular
focus
on
nature
and
frequency
upstream
aberrations.
Tumors
aberrations
maintain
dependency
presence
functional
ligand,
predicted
be
tractable
inhibitors
Porcupine,
an
enzyme
that
plays
key
role
in
secretion.
We
summarise
available
pre-clinical
efficacy
data
from
Porcupine
vitro
vivo,
as
well
potential
toxicities
early
phase
clinical
trials.
appraise
rationale
biomarker-defined
targeted
approaches,
outlining
future
opportunities
combination
therapeutics.
PLoS ONE,
Год журнала:
2023,
Номер
18(4), С. e0283894 - e0283894
Опубликована: Апрель 6, 2023
RNF43
is
an
important
negative
regulator
of
β-catenin
signaling
by
removing
Wnt-receptors
from
the
membrane.
It
often
mutated
in
cancers,
leading
to
aberrant
Wnt-dependent
nuclear
translocation
β-catenin.
has
also
been
suggested
regulate
directly
within
nucleus,
among
other
proposed
functions.
Given
importance
regulating
Wnt/β-catenin
and
its
potential
therapeutic
relevance,
a
proper
understanding
biology
required.
However,
presumed
location
mainly
based
on
available
antibodies.
These
same
antibodies
have
used
extensively
for
immunoblotting
or
immunohistochemical
purposes.
evaluation
their
quality
reliably
detect
endogenous
not
performed.
Here,
using
genome
editing
we
generated
cell
line
that
entirely
misses
exons
8
9,
encoding
epitopes
commonly
Using
this
clone
addition
various
tools,
show
four
only
yield
non-specific
signals
when
applied
immunoblotting,
immunofluorescence
experiments.
In
words,
they
cannot
RNF43.
Our
results
suggest
staining
patterns
are
antibody
artifact
unlikely
localize
nucleus.
More
generally,
reports
should
be
interpreted
with
caution,
at
least
protein
aspects
described
these
papers.
