Journal of Medicinal Chemistry,
Journal Year:
2022,
Volume and Issue:
65(20), P. 13561 - 13573
Published: Oct. 7, 2022
Extracellular
signal-regulated
protein
kinase
1/2
(ERK1/2),
the
only
known
substrate
of
MEK1/2,
is
located
downstream
RAS-RAF-MEK-ERK
(MAPK)
pathway
and
associated
with
abnormal
activation
poor
prognosis
cancer.
To
date,
several
small-molecule
inhibitors
RAS,
RAF,
MEK
have
been
reported
to
make
rapid
advances
in
cancer
therapy;
however,
acquired
resistance
still
occurs,
thereby
weakening
therapeutic
efficacy
these
inhibitors.
Recently,
selective
inhibition
ERK1/2
has
regarded
as
a
potential
strategy
that
can
not
effectively
block
MAPK
but
also
overcome
drug
caused
by
upstream
mutations
MEK.
Herein,
we
summarize
oncogenic
roles,
key
signaling
network,
single-
dual-target
preclinical
clinical
trials.
Together,
inspiring
findings
shed
new
light
on
discovery
more
candidate
drugs
improve
therapeutics.
Medicinal Research Reviews,
Journal Year:
2023,
Volume and Issue:
43(6), P. 1974 - 2024
Published: April 29, 2023
Abstract
Necroptosis
is
a
highly
regulated
cell
death
(RCD)
form
in
various
inflammatory
diseases.
Receptor‐interacting
protein
kinase
1
(RIPK1)
and
RIPK3
are
involved
the
pathway.
Targeting
domains
of
RIPK1
and/or
3
drug
design
strategy
for
related
It
generally
accepted
that
essential
reoccurring
features
observed
across
human
domains,
including
RIPK3.
They
present
common
N‐
C‐terminal
built
up
mostly
by
α‐helices
β‐sheets,
respectively.
The
current
RIPK1/3
inhibitors
mainly
interact
with
catalytic
cleft.
This
article
aims
to
an
in‐depth
profiling
ligand–kinase
interactions
crucial
cleft
areas
carefully
aligning
kinase‐ligand
cocrystal
complexes
or
molecular
docking
models.
similarity
differential
structural
segments
ligands
systematically
evaluated.
New
insights
on
adaption
conserved
selective
diversity
chemical
scaffolds
also
provided.
In
word,
our
analysis
can
provide
better
requirement
inhibition
guide
inhibitor
discovery
optimization
their
potency
selectivity.
ACS Chemical Biology,
Journal Year:
2023,
Volume and Issue:
18(10), P. 2101 - 2113
Published: June 29, 2023
Ribonucleases
(RNases)
cleave
and
process
RNAs,
thereby
regulating
the
biogenesis,
metabolism,
degradation
of
coding
noncoding
RNAs.
Thus,
small
molecules
targeting
RNases
have
potential
to
perturb
RNA
biology,
been
studied
as
therapeutic
targets
antibiotics,
antivirals,
agents
for
autoimmune
diseases
cancers.
Additionally,
recent
advances
in
chemically
induced
proximity
approaches
led
discovery
bifunctional
that
target
achieve
or
inhibit
processing.
Here,
we
summarize
efforts
made
discover
small-molecule
inhibitors
activators
bacterial,
viral,
human
RNases.
We
also
highlight
emerging
examples
RNase-targeting
discuss
trends
developing
such
both
biological
applications.
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(23), P. 21438 - 21469
Published: Dec. 3, 2024
Binding
multiple
sites
within
proteins
with
bivalent
compounds
is
a
strategy
for
developing
uniquely
active
agents.
A
new
class
of
dual-site
inhibitors
has
emerged
targeting
the
epidermal
growth
factor
receptor
(EGFR)
anchored
to
both
orthosteric
(ATP)
and
allosteric
sites.
Despite
proof-of-concept
successes,
enabling
selectivity
against
oncogenic
activating
mutations
not
been
achieved
classifying
these
among
kinase
remains
underexplored.
This
study
investigates
structure–activity
relationships,
binding
modes,
biological
activity
ATP-allosteric
(AABIs).
We
find
that
AABIs
selectively
inhibit
drug-resistant
EGFR
mutants
(L858R/T790M
L858R/T790M/C797S)
by
anchoring
methyl
isoindolinone
moiety
along
αC-helix
channel
site.
In
contrast,
related
Type
I1/2
target
wild-type
but
are
less
effective
resistant
mutants.
shift
in
demonstrates
mutant-selective
classify
as
"Type
V"
inhibitors.
