Targeted Covalent Modification Strategies for Drugging the Undruggable Targets
Chemical Reviews,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 7, 2025
The
term
"undruggable"
refers
to
proteins
or
other
biological
targets
that
have
been
historically
challenging
target
with
conventional
drugs
therapeutic
strategies
because
of
their
structural,
functional,
dynamic
properties.
Drugging
such
undruggable
is
essential
develop
new
therapies
for
diseases
where
current
treatment
options
are
limited
nonexistent.
Thus,
investigating
methods
achieve
drugging
an
important
challenge
in
medicinal
chemistry.
Among
the
numerous
methodologies
drug
discovery,
covalent
modification
has
emerged
as
a
transformative
strategy.
attachment
diverse
functional
molecules
provides
powerful
platform
creating
highly
potent
and
chemical
tools
well
ability
provide
valuable
information
on
structures
dynamics
targets.
In
this
review,
we
summarize
recent
examples
biomolecules
development
therapeutics
overcome
discovery
challenges
highlight
how
contribute
toward
particular,
focus
use
chemistry
drugs,
identification,
screening,
artificial
modulation
post-translational
modifications,
cancer
specific
chemotherapies,
nucleic
acid-based
therapeutics.
Язык: Английский
O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells
Journal of the American Chemical Society,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 27, 2025
Lysine
residue
represents
an
attractive
site
for
covalent
drug
development
due
to
its
high
abundance
(5.6%)
and
critical
functions.
However,
very
few
lysines
have
been
characterized
be
accessible
ligands
perturb
the
protein
functions,
owing
their
protonation
state
adjacent
steric
hindrance.
Herein,
we
report
a
new
lysine
bioconjugation
chemistry,
O-cyanobenzaldehyde
(CNBA),
that
enables
selective
modification
of
ε-amine
form
iso-indolinones
under
physiological
conditions.
Activity-based
proteome
profiling
enabled
mapping
3451
residues
85
endogenous
kinases
in
live
cells,
highlighting
potential
modifying
hyper-reactive
within
or
buried
catalytic
kinome.
Further
crystallography
mass
spectrometry
confirmed
K271_ABL1
K162_AURKA
are
covalently
targetable
sites
kinases.
Leveraging
structure-based
design,
incorporated
CNBA
into
core
structure
Nutlin-3
irreversibly
inhibit
MDM2-p53
interaction
by
targeting
exposed
K94
on
surface
murine
double
minute
2.
Importantly,
demonstrated
application
as
lysine-recognized
agent
developing
antibody-drug
conjugates.
The
results
collectively
validate
efficient
with
broad
applications
both
cells.
Язык: Английский
Unraveling Small Molecule-Mediated Sirtuin 3 Activation at a Distinct Binding Site for Cardioprotective Therapies
ACS Central Science,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 13, 2025
Sirtuin
3
(SIRT3),
a
pivotal
mitochondrial
deacetylase,
plays
critical
role
in
restoring
function,
particularly
through
the
activation
of
autophagy.
Despite
its
promise
as
cardioprotective
target,
developing
SIRT3
activators
and
their
therapeutic
applications
remains
challenging.
Here,
we
report
identification
SKLB-11A,
activator
with
submicromolar
affinity
high
efficacy.
Structural
mutagenesis
analyses
revealed
unique
allosteric
site
for
SKLB-11A
SIRT3,
where
conformational
change
Leu298
drives
potent
activation.
Subsequent
studies
demonstrated
that
autophagy/mitophagy
signaling
pathways,
effectively
preventing
dysfunction,
improving
cardiac
dysfunction
both
doxorubicin
(Dox)-induced
cardiotoxicity
myocardial
ischemia/reperfusion
(I/R)
models.
Collectively,
our
data
highlight
potential
pharmacological
an
effective
strategy
cardioprotection.
first-in-class
distinct
binding
mode,
not
only
offers
valuable
tool
exploring
physiological
pathological
roles
deacetylation
but
also
holds
development
targeted
therapies.
Язык: Английский
Advancing Covalent Ligand and Drug Discovery beyond Cysteine
Chemical Reviews,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 22, 2025
Targeting
intractable
proteins
remains
a
key
challenge
in
drug
discovery,
as
these
often
lack
well-defined
binding
pockets
or
possess
shallow
surfaces
not
readily
addressed
by
traditional
design.
Covalent
chemistry
has
emerged
powerful
solution
for
accessing
protein
sites
difficult
to
ligand
regions.
By
leveraging
activity-based
profiling
(ABPP)
and
LC-MS/MS
technologies,
academic
groups
industry
have
identified
cysteine-reactive
ligands
that
enable
selective
targeting
of
challenging
modulate
previously
inaccessible
biological
pathways.
Cysteines
within
are
rare,
however,
developing
covalent
target
additional
residues
hold
great
promise
further
expanding
the
ligandable
proteome.
This
review
highlights
recent
advancements
amino
acids
beyond
cysteine
with
an
emphasis
on
tyrosine-
lysine-directed
their
applications
chemical
biology
therapeutic
development.
We
outline
process
using
proteomic
methodology,
highlighting
successful
examples
discuss
considerations
future
expansion
acid
proteins.
Язык: Английский
Activity-Based Acylome Profiling with N-(Cyanomethyl)-N-(phenylsulfonyl)amides for Targeted Lysine Acylation and Post-Translational Control of Protein Function in Cells
Journal of the American Chemical Society,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 30, 2024
Lysine
acylations
are
ubiquitous
and
structurally
diverse
post-translational
modifications
that
vastly
expand
the
functional
heterogeneity
of
human
proteome.
Hence,
targeted
acylation
lysine
residues
has
emerged
as
a
strategic
approach
to
exert
biomimetic
control
over
protein
function.
However,
existing
strategies
for
in
cells
often
rely
on
genetic
intervention,
recruitment
endogenous
machinery,
or
nonspecific
acylating
agents
lack
methods
quantify
magnitude
specific
global
level.
In
this
study,
we
develop
activity-based
acylome
profiling
(ABAP),
chemoproteomic
strategy
exploits
elaborate
Язык: Английский