ChemBioChem,
Journal Year:
2023,
Volume and Issue:
25(7)
Published: Nov. 21, 2023
The
installation
of
aldehydes
into
synthetic
protein
ligands
is
an
efficient
strategy
to
engage
lysine
residues
in
remarkably
stable
imine
bonds
and
augment
the
compound
affinity
selectivity
for
their
biological
targets.
high
frequency
proteins
reversibility
covalent
ligand-protein
bond
support
application
aldehyde-bearing
ligands,
holding
promises
future
use
as
drugs.
This
review
highlights
increasing
exploitation
salicylaldehyde
modules
various
classes
binders,
aimed
at
reversible-covalent
engagement
residues.
Journal of Medicinal Chemistry,
Journal Year:
2023,
Volume and Issue:
66(14), P. 9297 - 9312
Published: July 5, 2023
Within
druggable
target
space,
new
small-molecule
modalities,
particularly
covalent
inhibitors
and
targeted
degraders,
have
expanded
the
repertoire
of
medicinal
chemists.
Molecules
with
such
modes
action
a
large
potential
not
only
as
drugs
but
also
chemical
probes.
Criteria
previously
been
established
to
describe
potency,
selectivity,
properties
probes
that
are
qualified
enable
interrogation
validation
drug
targets.
These
definitions
tailored
reversibly
acting
modulators
fall
short
in
their
applicability
other
modalities.
While
initial
guidelines
proposed,
we
delineate
here
full
set
criteria
for
characterization
covalent,
irreversible
well
heterobifunctional
degraders
("proteolysis-targeting
chimeras",
or
PROTACs)
molecular
glue
degraders.
We
propose
modified
potency
selectivity
compared
those
reversible
inhibitors.
discuss
relevance
highlight
examples
suitable
probe
pathfinder
compounds.
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(10), P. 7668 - 7758
Published: May 7, 2024
Covalent
inhibitors
and
other
types
of
covalent
modalities
have
seen
a
revival
in
the
past
two
decades,
with
variety
new
targeted
drugs
having
been
approved
recent
years.
A
key
feature
such
molecules
is
an
intrinsically
reactive
group,
typically
weak
electrophile,
which
enables
irreversible
or
reversible
formation
bond
specific
amino
acid
target
protein.
This
often
called
"warhead",
critical
determinant
ligand's
activity,
selectivity,
general
biological
properties.
In
2019,
we
summarized
emerging
re-emerging
warhead
chemistries
to
cysteine
acids
(Gehringer,
M.;
Laufer,
S.
A.
J.
Med.
Chem.
62,
5673−5724;
DOI:
10.1021/acs.jmedchem.8b01153).
Since
then,
field
has
rapidly
evolved.
Here
discuss
progress
on
warheads
made
since
our
last
Perspective
their
application
medicinal
chemistry
chemical
biology.
Journal of the American Chemical Society,
Journal Year:
2023,
Volume and Issue:
145(7), P. 3844 - 3849
Published: Feb. 12, 2023
Lysine-targeting
irreversible
covalent
inhibitors
have
attracted
growing
interests
in
recent
years,
especially
the
fields
of
kinase
research.
Despite
encouraging
progress,
few
chemistries
are
available
to
develop
that
exclusively
lysine-targeting,
selective,
and
cell-active.
We
report
herein
a
2-ethynylbenzaldehyde
(EBA)-based,
lysine-targeting
strategy
generate
potent
selective
small-molecule
ABL
by
selectively
targeting
conserved
catalytic
lysine
enzyme.
showed
resulting
compounds
were
cell-active,
capable
covalently
engaging
endogenous
K562
cells
with
long-residence
time
off-targets.
further
validated
generality
this
developing
EBA-based
against
EGFR
(a
kinase)
Mcl-1
nonkinase)
reacted
noncatalytic
within
each
target.
MedComm – Oncology,
Journal Year:
2023,
Volume and Issue:
2(4)
Published: Oct. 31, 2023
Abstract
Covalent
inhibitors
have
been
a
rapidly
growing
field
in
drug
discovery
due
to
their
therapeutic
potential
and
unique
advantages
cancer
therapy.
As
opposed
noncovalent
inhibitory
drugs,
covalent
reversibly
or
irreversibly
modify
proximal
nucleophilic
amino
acid
residues
on
proteins,
aiming
selectively
recognize
bind
protein
targets
addressing
some
of
the
challenges
faced
by
drugs.
Most
successful
targeted
depend
primarily
binding‐site
cysteine
residues,
but
this
has
limitations
for
certain
that
lack
targetable
residues.
Recently,
rational
design
probes
targeting
other
such
as
lysine,
tyrosine,
serine,
turned
out
be
another
promising
strategy
Thus,
development
novel
strategies
extend
scope
binding
improve
properties
is
required.
This
review
gives
summary
noncysteine
from
different
aspects,
including
target
identification,
structure–activity
relationships,
strategies,
properties,
hope
providing
scientific
reference
future
means
expanding
research
Angewandte Chemie International Edition,
Journal Year:
2024,
Volume and Issue:
63(12)
Published: Jan. 22, 2024
Abstract
Advances
in
targeted
covalent
inhibitors
(TCIs)
have
been
made
by
using
lysine‐reactive
chemistries.
Few
aminophiles
possessing
balanced
reactivity/stability
for
the
development
of
cell‐active
TCIs
are
however
available.
We
report
herein
activity‐based
probes
(ABPs;
2–14
)
based
on
chemistry
aryl
fluorosulfates
(ArOSO
2
F)
capable
global
reactivity
profiling
catalytic
lysine
human
kinome
from
mammalian
cells.
concurrently
developed
reversible
ABPs
(
15
/
16
installing
salicylaldehydes
(SA)
onto
a
promiscuous
kinase‐binding
scaffold.
The
stability
and
amine
these
exhibited
broad
range
tunability.
X‐ray
crystallography
mass
spectrometry
(MS)
confirmed
successful
engagement
between
ArOSO
F
9
SRC
kinase.
Chemoproteomic
studies
enabled
>300
endogenous
kinases,
thus
providing
landscape
ligandable
lysines
kinome.
By
further
introducing
into
VX‐680
(a
noncovalent
inhibitor
AURKA
kinase),
we
generated
novel
that
excellent
vitro
potency
reasonable
cellular
activities
with
prolonged
residence
time.
Our
work
serves
as
general
guide
F‐based
TCIs.
Chemical Society Reviews,
Journal Year:
2022,
Volume and Issue:
51(22), P. 9243 - 9261
Published: Jan. 1, 2022
This
review
summarizes
the
recent
work
of
covalent
chemistry
in
targeted
protein
degradation
and
describes
concept,
pros
cons,
development,
outlook
PROTACs.
Biochemical Journal,
Journal Year:
2023,
Volume and Issue:
480(16), P. 1331 - 1363
Published: Aug. 29, 2023
There
are
over
500
human
kinases
ranging
from
very
well-studied
to
almost
completely
ignored.
Kinases
tractable
and
implicated
in
many
diseases,
making
them
ideal
targets
for
medicinal
chemistry
campaigns,
but
is
it
possible
discover
a
drug
each
individual
kinase?
For
every
kinase,
we
gathered
data
on
their
citation
count,
availability
of
chemical
probes,
approved
investigational
drugs,
PDB
structures,
biochemical
cellular
assays.
Analysis
these
factors
highlights
which
kinase
groups
have
wealth
information
available,
still
room
progress.
The
suggest
disproportionate
focus
the
more
well
characterized
while
much
kinome
remains
comparatively
understudied.
It
noteworthy
that
tool
compounds
understudied
already
been
developed,
there
untapped
potential
further
development
this
space.
Finally,
review
discusses
different
strategies
employed
generate
selectivity
between
kinases.
Given
large
volume
available
progress
made
past
20
years
when
comes
drugging
kinases,
believe
develop
compound
kinase.
We
hope
will
prove
be
both
useful
resource
as
inspire
discovery
Communications Chemistry,
Journal Year:
2024,
Volume and Issue:
7(1)
Published: Feb. 14, 2024
Abstract
Covalent
probes
coupled
with
chemical
proteomics
represent
a
powerful
method
for
investigating
small
molecule
and
protein
interactions.
However,
the
creation
of
reactive
warhead
within
various
ligands
to
form
covalent
has
been
major
obstacle.
Herein,
we
report
convenient
robust
process
assemble
unique
electrophile,
an
α-
acyloxyenamide,
through
one-step
late-stage
coupling
reaction.
This
procedure
demonstrates
remarkable
tolerance
towards
other
functional
groups
facilitates
ligand-directed
labeling
in
proteins
interest.
The
group
successfully
incorporated
into
clinical
drug
targeting
EGFR
L858R
mutant,
erlotinib,
pan-kinase
inhibitor.
resulting
have
shown
be
able
covalently
engage
lysine
residue
proximal
ATP-binding
pocket
mutant.
A
series
active
sites,
Mg
2+
,
sites
kinases,
such
as
K33
CDK1,
CDK2,
CDK5
were
detected.
is
first
engaging
these
conserved
catalytic
residues
kinases
inhibition.
Further
application
this
methodology
natural
products
demonstrated
its
success
profiling
ligandable
whole
proteome.
These
findings
offer
insights
development
new
targeted
inhibitors
(TCIs).