Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(17), С. 14723 - 14741
Опубликована: Авг. 26, 2024
Murine
double
minute
X
(MDMX)
is
an
oncoprotein
that
mainly
has
a
negative
regulatory
effect
on
the
tumor
suppressor
p53
to
induce
tumorigenesis.
As
MDMX
highly
expressed
in
various
types
of
cells,
targeting
and
inhibiting
are
becoming
promising
strategy
for
treating
cancers.
However,
high
degree
structural
homology
between
its
homologous
protein
murine
2
(MDM2)
great
challenge
development
MDMX-targeted
therapies.
This
review
introduces
structure,
distribution,
regulation
MDMX,
summarizes
features
structure-activity
relationships
(SARs)
ligands,
focuses
differences
MDM2
these
aspects.
Our
purpose
this
work
propose
potential
strategies
achieve
specific
MDMX.
Journal of Medicinal Chemistry,
Год журнала:
2023,
Номер
66(14), С. 9401 - 9417
Опубликована: Июль 13, 2023
We
report
the
discovery
of
sulanemadlin
(ALRN-6924),
first
cell-permeating,
stabilized
α-helical
peptide
to
enter
clinical
trials.
ALRN-6924
is
a
"stapled
peptide"
that
mimics
N-terminal
domain
p53
tumor
suppressor
protein.
It
binds
with
high
affinity
both
MDM2
and
MDMX
(also
known
as
MDM4),
endogenous
inhibitors
p53,
activate
signaling
in
cells
having
non-mutant,
or
wild-type
TP53
genotype
(TP53-WT).
Iterative
structure-activity
optimization
endowed
favorable
cell
permeability,
solubility,
pharmacokinetic
safety
profiles.
Intracellular
proteolysis
forms
long-acting
active
metabolite
potent
binding
slow
dissociation
kinetics.
At
doses,
exhibits
on-mechanism
anticancer
activity
TP53-WT
models.
lower
transiently
arrests
cycle
healthy
tissues
protect
them
from
chemotherapy
without
protecting
TP53-mutant
cancer
cells.
These
results
support
continued
evaluation
an
chemoprotection
agent.
Biomolecules,
Год журнала:
2023,
Номер
13(11), С. 1653 - 1653
Опубликована: Ноя. 15, 2023
Cancer
is
a
complex
and
multifaceted
disease
with
high
global
incidence
mortality
rate.
Although
cancer
therapy
has
evolved
significantly
over
the
years,
numerous
challenges
persist
on
path
to
effectively
combating
this
disease.
Natural
compounds
derived
from
plants,
fungi,
or
marine
organisms
have
garnered
considerable
attention
as
potential
therapeutic
agents
in
field
of
research.
Ellagic
acid
(EA),
natural
polyphenolic
compound
found
various
fruits
nuts,
emerged
prevention
treatment
agent.
This
review
summarizes
experimental
evidence
supporting
role
EA
targeting
key
hallmarks
cancer,
including
proliferation,
angiogenesis,
apoptosis
evasion,
immune
inflammation,
genomic
instability,
more.
We
discuss
molecular
mechanisms
by
which
modulates
signaling
pathways
targets
involved
these
hallmarks,
based
vitro
vivo
studies.
The
actions
make
it
promising
candidate
for
therapy.
Understanding
its
impact
biology
can
pave
way
developing
novel
strategies
combat
Oncoscience,
Год журнала:
2024,
Номер
11, С. 1 - 14
Опубликована: Янв. 3, 2024
In
January
2023,
diagnosed
with
numerous
metastases
of
lung
cancer
in
my
brain,
I
felt
that
must
accomplish
a
mission.If
everything
happens
for
reason,
cancer,
particular,
find
out
how
metastatic
can
be
treated
curative
intent.This
is
mission
now,
and
the
reason
was
ever
born.In
understood
meaning
life,
life.I
born
to
write
this
article.In
article,
argue
monotherapy
targeted
drugs,
even
when
used
sequence,
cannot
cure
cancer.However,
preemptive
combinations
drugs
may,
theory,
incurable
cancer.Also,
share
insights
on
various
topics,
including
rapamycin,
an
anti-aging
drug
delay
but
not
prevent
through
personal
journey.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer,
Год журнала:
2024,
Номер
1879(4), С. 189124 - 189124
Опубликована: Май 25, 2024
Apoptosis
has
traditionally
been
regarded
as
the
desired
cell
death
pathway
activated
by
chemotherapeutic
drugs
due
to
its
controlled
and
non-inflammatory
nature.
However,
recent
discoveries
of
alternative
pathways
have
paved
way
for
immune-stimulatory
treatment
approaches
in
cancer.
Ferroptosis
(dependent
on
iron)
cuproptosis
copper)
hold
promise
selective
cancer
targeting
overcoming
drug
resistance.
Copper
ionophores
iron-bearing
nano-drugs
show
potential
clinical
therapy
single
agents
adjuvant
treatments.
Here
we
review
up-to-date
evidence
involvement
metal
ion-dependent
cytotoxicity
classical
(alkylating
agents,
topoisomerase
inhibitors,
antimetabolites,
mitotic
spindle
inhibitors)
their
combinations
with
ferroptosis
inducers,
indicating
prospects,
advantages,
obstacles
use.
Synthetic
data
generation
in
omics
mimics
real-world
biological
data,
providing
alternatives
for
training
and
evaluation
of
genomic
analysis
tools,
controlling
differential
expression,
exploring
architecture.
We
previously
developed
Precious1GPT,
a
multimodal
transformer
trained
on
transcriptomic
methylation
along
with
metadata,
predicting
age
identifying
dual-purpose
therapeutic
targets
potentially
implicated
aging
age-associated
diseases.
In
this
study,
we
introduce
Precious2GPT,
architecture
that
integrates
Conditional
Diffusion
(CDiffusion)
decoder-only
Multi-omics
Pretrained
Transformer
(MoPT)
models
gene
expression
DNA
data.
Precious2GPT
excels
synthetic
generation,
outperforming
Generative
Adversarial
Networks
(CGANs),
CDiffusion,
MoPT.
demonstrate
is
capable
generating
representative
captures
tissue-
age-specific
information
from
real
transcriptomics
methylomics
Notably,
surpasses
other
prediction
accuracy
using
the
generated
it
can
generate
beyond
120
years
age.
Furthermore,
showcase
potential
model
signatures
colorectal
cancer
case
study.
