ChemBioChem,
Journal Year:
2021,
Volume and Issue:
22(10), P. 1841 - 1851
Published: Jan. 15, 2021
Chemoproteomics
has
enabled
the
rapid
and
proteome-wide
discovery
of
functional,
redox-sensitive,
ligandable
cysteine
residues.
Despite
widespread
adoption
considerable
advances
in
both
sample-preparation
workflows
MS
instrumentation,
chemoproteomics
experiments
still
typically
only
identify
a
small
fraction
all
cysteines
encoded
by
human
genome.
Here,
we
develop
an
optimized
workflow
that
combines
enhanced
peptide
labeling
with
single-pot,
solid-phase-enhanced
(SP3)
to
improve
recovery
biotinylated
peptides,
even
from
sample
sizes.
By
combining
this
improved
on-line
high-field
asymmetric
waveform
ion
mobility
spectrometry
(FAIMS)
separation
labeled
achieve
unprecedented
coverage
>14000
unique
single-shot
70
min
experiment.
Showcasing
wide
utility
SP3-FAIMS
chemoproteomic
method,
find
it
is
also
compatible
competitive
small-molecule
screening
isotopic
tandem
orthogonal
proteolysis-activity-based
protein
profiling
(isoTOP-ABPP).
In
aggregate,
our
analysis
18
samples
seven
cell
lines
identified
34225
using
∼28
h
instrument
time.
The
comprehensive
spectral
library
provided
method
will
provide
technical
foundation
for
future
studies
aimed
at
deciphering
functions
druggability
cysteineome.
Nature,
Journal Year:
2023,
Volume and Issue:
616(7958), P. 673 - 685
Published: April 26, 2023
Computer-aided
drug
discovery
has
been
around
for
decades,
although
the
past
few
years
have
seen
a
tectonic
shift
towards
embracing
computational
technologies
in
both
academia
and
pharma.
This
is
largely
defined
by
flood
of
data
on
ligand
properties
binding
to
therapeutic
targets
their
3D
structures,
abundant
computing
capacities
advent
on-demand
virtual
libraries
drug-like
small
molecules
billions.
Taking
full
advantage
these
resources
requires
fast
methods
effective
screening.
includes
structure-based
screening
gigascale
chemical
spaces,
further
facilitated
iterative
approaches.
Highly
synergistic
are
developments
deep
learning
predictions
target
activities
lieu
receptor
structure.
Here
we
review
recent
advances
technologies,
potential
reshaping
whole
process
development,
as
well
challenges
they
encounter.
We
also
discuss
how
rapid
identification
highly
diverse,
potent,
target-selective
ligands
protein
can
democratize
process,
presenting
new
opportunities
cost-effective
development
safer
more
small-molecule
treatments.
Recent
approaches
application
streamlining
discussed.
Accounts of Chemical Research,
Journal Year:
2021,
Volume and Issue:
54(7), P. 1801 - 1813
Published: March 18, 2021
ConspectusOne
of
the
biggest
bottlenecks
in
modern
drug
discovery
efforts
is
tackling
undruggable
proteome.
Currently,
over
85%
proteome
still
considered
because
most
proteins
lack
well-defined
binding
pockets
that
can
be
functionally
targeted
with
small
molecules.
Tackling
necessitates
innovative
approaches
for
ligand
against
as
well
development
new
therapeutic
modalities
to
manipulate
interest.
Chemoproteomic
platforms,
particular
activity-based
protein
profiling
(ABPP),
have
arisen
tackle
by
using
reactivity-based
chemical
probes
and
advanced
quantitative
mass
spectrometry-based
proteomic
enable
"ligandable
hotspots"
or
proteome-wide
sites
small-molecule
ligands.
These
subsequently
pharmacologically
covalent
ligands
rapidly
discover
functional
nonfunctional
binders
also
revealed
unique
insights
into
ligandability
such
allosteric
intrinsically
disordered
regions
selectively
biological
modulation
benefit.
platforms
expanded
scope
emerging
degradation
proteolysis-targeting
chimeras
(PROTACs)
through
several
E3
ligase
recruiters.
Looking
future,
chemoproteomic
will
unquestionably
a
major
impact
further
expansion
existing
toward
mapping,
high-value
targets,
molecular
glue
scaffolds
function,
perhaps
excitingly
next-generation
induced-proximity-based
go
beyond
degradation.
Exciting
days
lie
ahead
this
field
biology
becomes
an
increasingly
driver
discovery,
are
sure
mainstay
developing
therapeutics.
Journal of Proteome Research,
Journal Year:
2023,
Volume and Issue:
22(7), P. 2151 - 2171
Published: June 1, 2023
Mass
spectrometry
is
unmatched
in
its
versatility
for
studying
practically
any
aspect
of
the
proteome.
Because
foundations
mass
spectrometry-based
proteomics
are
complex
and
span
multiple
scientific
fields,
can
be
perceived
as
having
a
high
barrier
to
entry.
This
tutorial
intended
an
accessible
illustrated
guide
technical
details
relatively
simple
quantitative
proteomic
experiment.
An
attempt
made
explain
relevant
concepts
those
with
limited
knowledge
basic
understanding
proteins.
experimental
overview
provided,
from
beginning
sample
preparation
analysis
protein
group
quantities,
explanations
how
data
acquired,
processed,
analyzed.
A
selection
advanced
topics
briefly
surveyed
works
further
reading
cited.
To
conclude,
brief
discussion
future
given,
considering
next-generation
sequencing
technologies
that
may
complement
create
fruitful
proteomics.
Cancer Discovery,
Journal Year:
2022,
Volume and Issue:
12(6), P. 1500 - 1517
Published: April 4, 2022
Covalent
inhibitors
of
KRASG12C
have
shown
antitumor
activity
against
advanced/metastatic
KRASG12C-mutated
cancers,
though
resistance
emerges
and
additional
strategies
are
needed
to
improve
outcomes.
JDQ443
is
a
structurally
unique
covalent
inhibitor
GDP-bound
that
forms
novel
interactions
with
the
switch
II
pocket.
potently
inhibits
KRASG12C-driven
cellular
signaling
demonstrates
selective
antiproliferative
in
cell
lines,
including
those
G12C/H95
double
mutations.
In
vivo,
induces
AUC
exposure-driven
efficacy
cell-derived
(CDX)
patient-derived
(PDX)
tumor
xenografts.
PDX
models,
single-agent
enhanced
by
combination
SHP2,
MEK,
or
CDK4/6.
Notably,
benefit
plus
SHP2
TNO155
maintained
at
reduced
doses
either
agent
CDX
consistent
mechanistic
synergy.
clinical
development
as
monotherapy
TNO155,
both
showing
patients
tumors.
binding
mode
potent
lines
vivo
models.
preclinical
models
malignancies,
shows
TNO155.
This
article
highlighted
Issue
feature,
p.
1397.
