Cancer Discovery,
Journal Year:
2020,
Volume and Issue:
10(8), P. 1129 - 1139
Published: May 19, 2020
Most
patients
with
KRAS
G12C-mutant
non-small
cell
lung
cancer
(NSCLC)
experience
clinical
benefit
from
selective
KRASG12C
inhibition,
whereas
colorectal
bearing
the
same
mutation
rarely
respond.
To
investigate
cause
of
limited
efficacy
inhibitors
in
cancer,
we
examined
effects
AMG510
G12C
lines.
Unlike
NSCLC
lines,
models
have
high
basal
receptor
tyrosine
kinase
(RTK)
activation
and
are
responsive
to
growth
factor
stimulation.
In
inhibition
induces
higher
phospho-ERK
rebound
than
cells.
Although
upstream
several
RTKs
interferes
blockade,
identify
EGFR
signaling
as
dominant
mechanism
resistance
inhibitors.
The
combinatorial
targeting
is
highly
effective
cells
patient-derived
organoids
xenografts,
suggesting
a
novel
therapeutic
strategy
treat
cancer.
SIGNIFICANCE:
lineage-specific.
RTK
dependency
kinetics
responsible
for
sensitivity
or
should
be
concomitantly
inhibited
overcome
blockade
tumors.See
related
commentary
by
Koleilat
Kwong,
p.
1094.This
article
highlighted
This
Issue
feature,
1079.
Journal of Medicinal Chemistry,
Journal Year:
2020,
Volume and Issue:
63(13), P. 6679 - 6693
Published: April 6, 2020
Capping
off
an
era
marred
by
drug
development
failures
and
punctuated
waning
interest
presumed
intractability
toward
direct
targeting
of
KRAS,
new
technologies
strategies
are
aiding
in
the
target's
resurgence.
As
previously
reported,
tetrahydropyridopyrimidines
were
identified
as
irreversible
covalent
inhibitors
KRASG12C
that
bind
switch-II
pocket
KRAS
make
a
bond
to
cysteine
12.
Using
structure-based
design
conjunction
with
focused
vitro
absorption,
distribution,
metabolism
excretion
screening
approach,
analogues
synthesized
increase
potency
reduce
metabolic
liabilities
this
series.
The
discovery
clinical
candidate
MRTX849
potent,
selective
inhibitor
is
described.
Journal of Medicinal Chemistry,
Journal Year:
2021,
Volume and Issue:
65(4), P. 3123 - 3133
Published: Dec. 10, 2021
KRASG12D,
the
most
common
oncogenic
KRAS
mutation,
is
a
promising
target
for
treatment
of
solid
tumors.
However,
when
compared
to
KRASG12C,
selective
inhibition
KRASG12D
presents
significant
challenge
due
requirement
inhibitors
bind
with
high
enough
affinity
obviate
need
covalent
interactions
mutant
protein.
Here,
we
report
discovery
and
characterization
first
noncovalent,
potent,
inhibitor,
MRTX1133,
which
was
discovered
through
an
extensive
structure-based
activity
improvement
shown
be
efficacious
in
xenograft
mouse
tumor
model.
New England Journal of Medicine,
Journal Year:
2021,
Volume and Issue:
384(25), P. 2382 - 2393
Published: June 23, 2021
Clinical
trials
of
the
KRAS
inhibitors
adagrasib
and
sotorasib
have
shown
promising
activity
in
cancers
harboring
glycine-to-cysteine
amino
acid
substitutions
at
codon
12
(KRAS
Signal Transduction and Targeted Therapy,
Journal Year:
2023,
Volume and Issue:
8(1)
Published: March 1, 2023
The
TP53
tumor
suppressor
is
the
most
frequently
altered
gene
in
human
cancers,
and
has
been
a
major
focus
of
oncology
research.
p53
protein
transcription
factor
that
can
activate
expression
multiple
target
genes
plays
critical
roles
regulating
cell
cycle,
apoptosis,
genomic
stability,
widely
regarded
as
"guardian
genome".
Accumulating
evidence
shown
also
regulates
metabolism,
ferroptosis,
microenvironment,
autophagy
so
on,
all
which
contribute
to
suppression.
Mutations
not
only
impair
its
function,
but
confer
oncogenic
properties
mutants.
Since
mutated
inactivated
malignant
tumors,
it
very
attractive
for
developing
new
anti-cancer
drugs.
However,
until
recently,
was
considered
an
"undruggable"
little
progress
made
with
p53-targeted
therapies.
Here,
we
provide
systematic
review
diverse
molecular
mechanisms
signaling
pathway
how
mutations
impact
progression.
We
discuss
key
structural
features
inactivation
by
mutations.
In
addition,
efforts
have
therapies,
challenges
encountered
clinical
development.
