bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 1, 2025
Abstract
Missense
mutations
in
PTPN11
,
the
gene
encoding
protein
tyrosine
phosphatase
SHP2,
are
common
several
developmental
disorders
and
cancers.
While
many
SHP2
disrupt
auto-inhibition
cause
hyperactivity,
do
not
enhance
catalytic
activity.
Both
activating
non-activating
could
potentially
drive
pathogenic
signaling
by
altering
protein-protein
interactions
or
subcellular
localization.
We
employed
proximity-labeling
proteomics
to
map
interaction
networks
of
wild-type
ten
clinically-relevant
mutants,
bound
an
inhibitor
that
stabilizes
its
auto-inhibited
state.
Our
analyses
revealed
mutation-and
inhibitor-dependent
alterations
interactome,
with
mutants
also
showing
changes
In
particular,
some
had
increased
mitochondrial
localization
impacted
function.
This
study
provides
a
rich
resource
for
exploring
offers
new
insights
into
molecular
basis
SHP2-driven
diseases.
Furthermore,
this
work
highlights
capacity
detect
missense-mutation-dependent
Signal Transduction and Targeted Therapy,
Journal Year:
2023,
Volume and Issue:
8(1)
Published: Sept. 6, 2023
Abstract
Undruggable
proteins
are
a
class
of
that
often
characterized
by
large,
complex
structures
or
functions
difficult
to
interfere
with
using
conventional
drug
design
strategies.
Targeting
such
undruggable
targets
has
been
considered
also
great
opportunity
for
treatment
human
diseases
and
attracted
substantial
efforts
in
the
field
medicine.
Therefore,
this
review,
we
focus
on
recent
development
discovery
targeting
“undruggable”
their
application
clinic.
To
make
review
well
organized,
discuss
strategies
proteins,
including
covalent
regulation,
allosteric
inhibition,
protein–protein/DNA
interaction
targeted
nucleic
acid-based
approach,
immunotherapy
others.
Science Bulletin,
Journal Year:
2024,
Volume and Issue:
69(11), P. 1776 - 1797
Published: March 29, 2024
Undruggable
targets
typically
refer
to
a
class
of
therapeutic
that
are
difficult
target
through
conventional
methods
or
have
not
yet
been
targeted,
but
great
clinical
significance.
According
statistics,
over
80%
disease-related
pathogenic
proteins
cannot
be
targeted
by
current
treatment
methods.
In
recent
years,
with
the
advancement
basic
research
and
new
technologies,
development
various
technologies
mechanisms
has
brought
perspectives
overcome
challenging
drug
targets.
Among
them,
protein
degradation
technology
is
breakthrough
strategy
for
This
can
specifically
identify
directly
degrade
utilizing
inherent
pathways
within
cells.
form
includes
types
such
as
proteolysis
targeting
chimera
(PROTAC),
molecular
glue,
lysosome-targeting
Chimaera
(LYTAC),
autophagosome-tethering
compound
(ATTEC),
autophagy-targeting
(AUTAC),
(AUTOTAC),
degrader-antibody
conjugate
(DAC).
article
systematically
summarizes
application
in
degraders
Finally,
looks
forward
future
direction
prospects
technology.
Chemical Reviews,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 10, 2025
Conditional
control
of
protein
activity
is
important
in
order
to
elucidate
the
particular
functions
and
interactions
proteins,
their
regulators,
substrates,
as
well
impact
on
behavior
a
cell
or
organism.
Optical
provides
perhaps
optimal
means
introducing
spatiotemporal
over
function
it
allows
for
tunable,
rapid,
noninvasive
activation
its
native
environment.
One
method
optical
through
introduction
photocaged
photoswitchable
noncanonical
amino
acids
(ncAAs)
genetic
code
expansion
cells
animals.
Genetic
incorporation
photoactive
ncAAs
at
key
residues
tool
activation,
sometimes
deactivation,
activity.
Importantly,
site
can
typically
be
rationally
selected
based
structural,
mechanistic,
computational
information.
In
this
review,
we
comprehensively
summarize
applications
lysine,
tyrosine,
cysteine,
serine,
histidine,
glutamate,
aspartate
derivatives,
phenylalanine
analogues.
The
extensive
diverse
list
proteins
that
have
been
placed
under
demonstrates
broad
applicability
methodology.
Journal of Medicinal Chemistry,
Journal Year:
2023,
Volume and Issue:
66(19), P. 13384 - 13399
Published: Sept. 29, 2023
Protein
tyrosine
phosphatase
SHP2
mediates
RAS-driven
MAPK
signaling
and
has
emerged
in
recent
years
as
a
target
of
interest
oncology,
both
for
treating
with
single
agent
combination
KRAS
inhibitor.
We
were
drawn
to
the
pharmacological
potential
inhibition,
especially
following
initial
observation
that
drug-like
compounds
could
bind
an
allosteric
site
enforce
closed,
inactive
state
enzyme.
Here,
we
describe
identification
characterization
GDC-1971
(formerly
RLY-1971),
inhibitor
currently
clinical
trials
G12C
divarasib
(GDC-6036)
treatment
solid
tumors
driven
by
mutation.
Diabetes,
Journal Year:
2024,
Volume and Issue:
73(5), P. 780 - 796
Published: Feb. 23, 2024
Increasing
evidence
implicates
chronic
inflammation
as
the
main
pathological
cause
of
diabetic
nephropathy
(DN).
Exploration
key
targets
in
inflammatory
pathway
may
provide
new
treatment
options
for
DN.
We
aimed
to
investigate
role
Src
homology
2–containing
protein
tyrosine
phosphatase
2
(SHP2)
macrophages
and
its
association
with
The
upregulated
phosphorylation
SHP2
was
detected
both
patients
diabetes
a
mouse
model.
Using
macrophage-specific
SHP2-knockout
(SHP2-MKO)
mice
SHP2fl/fl
injected
streptozotocin
(STZ),
we
showed
that
SHP2-MKO
significantly
attenuated
renal
dysfunction,
collagen
deposition,
fibrosis,
response
STZ-induced
diabetes.
RNA-sequencing
analysis
using
primary
peritoneal
(MPMs)
deletion
mainly
affected
mitogen-activated
kinase
(MAPK)
nuclear
factor-κB
(NF-κB)
signaling
pathways
well
MAPK/NF-κB–dependent
cytokine
release
MPMs.
Further
study
indicated
SHP2-deficient
failed
cytokines
induce
phenotypic
transition
fibrosis
cells.
Administration
pharmacological
inhibitor,
SHP099,
remarkably
protected
kidneys
type
1
mice.
In
conclusion,
these
results
identify
macrophage
accelerator
DN
suggest
inhibition
be
therapeutic
option
Article
Highlights
International Journal of Molecular Sciences,
Journal Year:
2022,
Volume and Issue:
23(24), P. 15944 - 15944
Published: Dec. 15, 2022
SH2
(Src
Homology
2)
domains
are
among
the
best
characterized
and
most
studied
protein-protein
interaction
(PPIs)
modules
able
to
bind
recognize
sequences
presenting
a
phosphorylated
tyrosine.
This
post-translational
modification
is
key
regulator
of
plethora
physiological
molecular
pathways
in
eukaryotic
cell,
so
possess
fundamental
role
cell
signaling.
Consequently,
several
pathologies
arise
from
dysregulation
such
SH2-domains
mediated
PPIs.
In
this
review,
we
recapitulate
current
knowledge
about
structural,
folding
stability,
binding
properties
their
roles
pathogenesis.
Moreover,
focus
attention
on
different
strategies
employed
modulate/inhibit
binding.
Altogether,
information
gathered
points
evidence
that
pharmacological
interest
highly
strategic
developing
new
therapeutics.
deeper
understanding
determinants
thermodynamic
stability
as
well
appears
be
order
improve
possibility
preventing
dysregulated
interactions.
Cancers,
Journal Year:
2023,
Volume and Issue:
15(20), P. 5015 - 5015
Published: Oct. 17, 2023
Pancreatic
ductal
adenocarcinoma
(PDAC)
remains
an
important
cause
of
cancer-related
mortality,
and
it
is
expected
to
play
even
bigger
part
in
cancer
burden
the
years
come.
Despite
concerted
efforts
from
scientists
physicians,
patients
have
experienced
little
improvement
survival
over
past
decades,
possibly
because
non-specific
nature
tested
treatment
modalities.
Recently,
discovery
potentially
targetable
molecular
alterations
has
paved
way
for
personalized
PDAC.
Indeed,
central
piece
framework
PDAC
starting
be
unveiled.
KRAS
mutations
are
seen
90%
PDACs,
multiple
studies
demonstrated
their
pivotal
role
pancreatic
carcinogenesis.
Recent
investigations
shed
light
on
differences
prognosis
as
well
therapeutic
implications
different
disentangled
relationship
between
effectors
downstream
parallel
signaling
pathways.
Additionally,
recognition
other
mechanisms
involving
KRAS-mediated
pathogenesis,
such
dosing
allelic
imbalance,
contributed
broadening
current
knowledge
regarding
this
alteration.
Finally,
G12C
inhibitors
been
recently
with
relative
success,
harboring
under
clinical
development.
These
drugs
currently
represent
a
true
hope
meaningful
leap
forward
dreadful
disease.
Frontiers in Oncology,
Journal Year:
2023,
Volume and Issue:
13
Published: June 16, 2023
The
Programmed
death-1
(PD-1)
and
its
programmed
death-ligand
1
(PD-L1)
comprise
the
PD-1/PD-L1
axis
maintain
tumor
immune
evasion.
Cancer
immunotherapy
based
on
anti-PD-1/PD-L1
antibodies
is
most
promising
anti-tumor
treatment
available
but
currently
facing
thorny
problem
of
unsatisfactory
outcomes.
Traditional
Chinese
Medicine
(TCM),
with
rich
heritage
medicine
monomers,
herbal
formulas,
physical
therapies
like
acupuncture,
moxibustion,
catgut
implantation,
a
multi-component
multi-target
system
known
for
enhancing
immunity
preventing
spread
disease.
TCM
often
used
as
an
adjuvant
therapy
cancer
in
clinical
practices,
recent
studies
have
demonstrated
synergistic
effects
combining
immunotherapy.
In
this
review,
we
examined
role
escape
while
exploring
how
can
modulate
to
improve
efficacy
Our
findings
suggest
that
enhance
by
reducing
expression
PD-1
PD-L1,
regulating
T-cell
function,
improving
microenvironment,
intestinal
flora.
We
hope
review
may
serve
valuable
resource
future
sensitization
checkpoint
inhibitors
(ICIs)
therapy.