In vitro and in vivo ADME of heterobifunctional degraders: a tailored approach to optimize DMPK properties of PROTACs©
RSC Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
This
study
suggests
a
tailored
in
vitro
DMPK
discovery
assay
cascade
and
frontloading
vivo
studies.
It
also
underlines
the
need
for
inclusion
of
surrogate
permeability
descriptors
experimentally
determined
values
IVIVE
CL
int
.
Язык: Английский
Identification of E3 ubiquitin ligase-associated prognostic genes and construction of a prediction model for uterine cervical cancer based on bioinformatics analysis
Discover Oncology,
Год журнала:
2024,
Номер
15(1)
Опубликована: Авг. 31, 2024
E3
ligases
are
engaged
in
a
variety
of
physiological
processes
within
cells
and
use
ubiquitin-labeled
substrates
to
control
their
activity
stability.
Although
some
research
has
indicated
that
or
particular
have
an
impact
on
the
treatment
cervical
cancer
patients
get
after
diagnosis,
The
exact
purpose
these
enzymes
occurrence
evolution
region
(CC)
is
not
clear.
In
order
extract
analyze
relevant
mRNA
gene
expression
data
as
well
clinical
patient
data,
we
used
open
databases.
A
reliable
risk
prediction
model
was
developed
by
applying
least
absolute
shrinkage
selection
operator
(LASSO)
technique
conjunction
with
Cox
regression
analysis.
Column-line
plots
were
combined
predictive
model,
GSE44001
dataset
served
external
validation.Four
models:proteasome
(prosome,
macropain)
26S
subunit,
non-ATPase,
14(PSMD14),proteasome
alpha
type,
4(PSMA4,),zinc
finger
BTB
domain
containing
16(ZBTB16),and
ankyrin
repeat
9(ANKRD9).
Gene
levels
both
healthy
cancerous
tissues
been
confirmed
HPA
database.
Next,
investigation
focused
immunological
state
tumor
mutation
load.
high-risk
group
Cluster
B
had
distinct
immune
cell
infiltration
worse
prognosis.
Additionally,
KEGG
GO
analyses
differentially
expressed
genes
(DEGs)
between
high-
low-risk
groups
performed,
microenvironment
(TME)
investigations.
Targeting
may
be
efficient
strategy
treat
(CC),
according
novel
comprehensive
ubiquitination
ligase-associated
presented.
Язык: Английский
Research progress of BRD4 in head and neck squamous cell carcinoma: Therapeutic application of novel strategies and mechanisms
Bioorganic & Medicinal Chemistry,
Год журнала:
2024,
Номер
113, С. 117929 - 117929
Опубликована: Сен. 19, 2024
Язык: Английский
Proteolysis Targeting Chimera Agents (PROTACs): New Hope for Overcoming the Resistance Mechanisms in Oncogene-Addicted Non-Small Cell Lung Cancer
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(20), С. 11214 - 11214
Опубликована: Окт. 18, 2024
Non-small
cell
lung
cancer
(NSCLC)
remains
a
disease
with
poor
prognosis
despite
the
advances
in
therapies.
NSCLC
actionable
oncogenic
alterations
represent
subgroup
of
diseases
for
which
tyrosine
kinase
inhibitors
(TKIs)
have
shown
relevant
and
robust
impact
on
prognosis,
both
early
advanced
stages.
While
introduction
powerful
TKIs
increases
ratio
potentially
curable
patients,
does
develop
resistance
over
time
through
either
secondary
mutations
or
bypass
activating
tracks.
Therefore,
new
treatment
strategies
are
being
developed
to
overcome
this
inevitable
prevent
it,
proteolysis
targeting
chimera
agents
(PROTACs)
among
them.
They
consist
two
linked
molecules
that
bind
target
protein
an
E3
ubiquitin
ligase
causes
ubiquitination
degradation
proteins
interest.
In
paper,
we
review
rationale
PROTAC
therapy
current
development
PROTACs
oncogene-addicted
cancer.
Moreover,
critically
analyze
strengths
limitations
promising
technique
may
help
pave
way
future
perspectives.
Язык: Английский
PROTACs in platelets: emerging antithrombotic strategies and future perspectives
Current Opinion in Hematology,
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 21, 2024
Purpose
of
review
Proteolysis-targeted
chimeras
(PROTACs)
are
heterobifunctional
compounds
that
selectively
target
proteins
for
degradation
and
an
emerging
therapeutic
modality
to
treat
diseases
such
as
cancer
neurodegenerative
disorders.
This
will
widen
the
area
application
by
highlighting
ability
PROTACs
remove
from
anucleate
platelets
evaluate
their
antithrombotic
potential.
Recent
findings
Proteomic
biochemical
studies
demonstrated
human
possess
Ubiquitin
Proteasomal
System
well
E3
ligase
cereblon
(CRBN)
therefore
may
be
susceptible
PROTAC-mediated
protein
degradation.
confirmed
CRBN
ligand-based
targeting
generic
tyrosine
kinases,
Btk
and/or
Fak
lead
efficacious
selective
in
platelets.
Downregulation
Btk,
a
key
player
involved
signalling
thrombosis,
but
not
haemostasis,
resulted
impaired
in-vitro
thrombus
formation.
Summary
Platelets
targeted
have
limited
resynthesise
proteins,
ensuring
long-term
downregulation
proteins.
Therefore,
serve
additional
research
tool
study
platelet
function
offer
new
potential
prevent
thrombosis.
Future
should
focus
on
enhancing
cell
specificity
avoid
on-target
side
effects
other
blood
cells.
Язык: Английский