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.
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.
Journal of the American Chemical Society,
Journal Year:
2024,
Volume and Issue:
146(35), P. 24233 - 24237
Published: Aug. 23, 2024
The
development
of
electrophilic
ligands
that
rapidly
modify
specific
lysine
residues
remains
a
major
challenge.
Salicylaldehyde-based
inhibitors
have
been
reported
to
form
stable
imine
adducts
with
the
catalytic
protein
kinases.
However,
targeted
in
these
examples
is
buried
hydrophobic
environment.
A
key
unanswered
question
whether
this
strategy
can
be
applied
on
surface
protein,
where
rapid
hydrolysis
resulting
salicylaldimine
more
likely.
Here,
we
describe
series
aminomethyl-substituted
salicylaldehydes
target
fully
solvated
ATPase
domain
Hsp90.
By
systematically
varying
orientation
salicylaldehyde,
discovered
long
residence
times,
best
which
engages
Hsp90
quasi-irreversible
manner.
Crystallographic
analysis
revealed
daisy-chain
network
intramolecular
hydrogen
bonds
locked
into
position
by
adjacent
piperidine
linker.
This
study
highlights
potential
aminomethyl
generate
conformationally
stabilized,
hydrolysis-resistant
imines,
even
when
far
from
ligand
binding
site
and
exposed
bulk
solvent.
ACS Medicinal Chemistry Letters,
Journal Year:
2025,
Volume and Issue:
16(3), P. 397 - 405
Published: Feb. 28, 2025
The
use
of
Targeted
Covalent
Inhibitors
(TCIs)
is
an
expanding
strategy
for
the
development
innovative
drugs.
It
driven
by
two
fundamental
steps:
(1)
recognition
target
site
molecule
and
(2)
establishment
covalent
interaction
its
reactive
group.
new
TCIs
depends
on
warheads.
Here,
we
propose
Morita–Baylis–Hillman
adducts
(MBHAs)
to
covalently
bind
Lys
strategically
placed
inside
a
lipophilic
pocket.
A
human
cellular
retinoic
acid
binding
protein
II
mutant
(M2)
was
selected
as
test
bench
library
19
MBHAs.
noncovalent
step
investigated
molecular
docking
studies,
while
experimentally
entire
incubated
with
M2
crystallized
confirm
lysine.
results,
rationalized
through
analysis,
support
our
hypothesis
MBHAs
scaffolds
design
lysine-TCIs.
Journal of the American Chemical Society,
Journal Year:
2023,
Volume and Issue:
145(48), P. 26202 - 26212
Published: Nov. 21, 2023
The
covalent
inhibition
of
a
target
protein
has
gained
widespread
attention
in
the
field
drug
discovery.
Most
current
drugs
utilize
high
reactivity
cysteines
toward
modest
electrophiles.
However,
there
is
growing
need
for
warheads
that
can
lysine
residues
to
expand
range
covalently
druggable
proteins
and
deal
with
emerging
mutations
resistant
cysteine-targeted
drugs.
We
have
recently
developed
an
N-acyl-N-alkyl
sulfonamide
(NASA)
as
lysine-targeted
electrophile.
Despite
its
successful
application,
this
NASA
warhead
suffered
from
instability
physiological
environments,
such
serum-containing
medium,
because
intrinsic
reactivity.
In
study,
we
sought
modify
structure
found
N-acyl-N-aryl
sulfonamides
(ArNASAs)
are
promising
electrophiles
use
strategy.
prepared
focused
library
ArNASA
derivatives
diverse
structures
identified
several
candidates
suppressed
hydrolysis-mediated
inactivation
reduced
nonspecific
reactions
off-target
proteins,
without
sacrificing
target.
These
reaction
properties
enabled
improved
intracellular
heat
shock
90
(HSP90)
presence
serum
development
first
irreversible
inhibitor
ibrutinib-resistant
Bruton's
tyrosine
kinase
(BTK)
bearing
C481S
mutation.
This
study
clearly
demonstrated
set
create
highly
potent
highlighted
importance
enriching
arsenal
lysine-reactive
warheads.
Journal of the American Chemical Society,
Journal Year:
2024,
Volume and Issue:
146(34), P. 23978 - 23988
Published: Aug. 20, 2024
Reversible
lysine
acetylation
is
an
important
post-translational
modification
(PTM).
This
process
in
cells
typically
carried
out
enzymatically
by
acetyltransferases
and
deacetylases.
The
catalytic
the
human
kinome
highly
conserved
ligandable.
Small-molecule
strategies
that
enable
of
on
kinases
a
target-selective
manner
therefore
provide
tremendous
potential
kinase
biology.
Herein,
we
report
first
small
molecule-induced
chemical
strategy
capable
global
from
mammalian
cells.
By
surveying
various
lysine-acetylating
agents
installed
promiscuous
kinase-binding
scaffold,
Ac4
was
identified
shown
to
effectively
acetylate
>100
different
protein
live
Jurkat/K562
In
order
demonstrate
this
reversible
kinases,
further
developed
six
acetylating
compounds
basis
VX-680
(a
noncovalent
inhibitor
AURKA).
Among
them,
Ac13/Ac14,
while
displaying
excellent
vitro
potency
sustained
cellular
activity
against
AURKA,
showed
robust
its
(K162)
manner,
leading
irreversible
inhibition
endogenous
activity.
reversibility
confirmed
Ac14-treated
recombinant
AURKA
protein,
followed
deacetylation
with
SIRT3
deacetylase).
Finally,
Ac13-induced
demonstrated
SIRT3-transfected
HCT116
disclosing
cell-active
both
our
could
useful
tool
biology
drug
discovery.
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 19, 2024
Targeting
the
lysine
residue
of
protein
kinases
to
develop
covalent
inhibitors
is
an
emerging
hotspot.
Herein,
we
have
reported
approach
lysine-targeted
PI3Kδ
by
in
situ
interaction
upgradation
H-bonding
bonding.
Several
warhead
groups
were
introduced
and
screened
situ,
leading
bearing
aromatic
esters
with
high
bioactivity
selectivity.
Compound
A11
phenolic
ester
was
finally
optimized
show
a
long
duration
action
SU-DHL-6
cells
multiple
assays.
Docking
simulation
further
mass
spectrometry
confirmed
that
bound
covalent-bonding
interactions
Lys779.
Furthermore,
exhibited
potently
antitumor
efficacy
without
obvious
toxicity
Pfeiffer
xenograft
mouse
models.
This
study
identified
be
much
more
effective
agent
vitro
vivo
as
inhibitor,
it
also
provided
practical
for
development
inhibitors.
Journal of the American Chemical Society,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 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.