Discovery of The Clinical Candidate S-892216: A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 28, 2025
Abstract
The
coronavirus
disease
2019
(COVID-19)
pandemic
crisis
has
been
mitigated
by
worldwide
efforts
to
develop
vaccines
and
therapeutic
drugs.
However,
there
remains
concern
regarding
public
health
an
unmet
need
for
options.
Herein,
we
report
the
discovery
of
S-892216
,
a
second-generation
SARS-CoV-2
3C-like
protease
(3CL
pro
)
inhibitor,
treat
COVID-19.
is
reversible
covalent
3CL
inhibitor
with
highly
potent
antiviral
activity
EC
50
value
2.48
nM
against
infected
cells.
Structure-based
design
modifier
compound
1
revealed
that
introducing
nitrile
warhead
increased
inhibition
180-fold.
Subsequent
optimization
yielded
which
combined
favorable
pharmacokinetic
profile
high
off-target
selectivity.
exhibited
diverse
variants,
no
cross-resistance
major
mutations
reducing
activities
nirmatrelvir
ensitrelvir.
In
SARS-CoV-2-infected
mice,
inhibited
viral
replication
in
lungs
similar
ensitrelvir,
although
at
30-fold
lower
dose.
Язык: Английский
Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality?
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(11), С. 6099 - 6099
Опубликована: Июнь 1, 2024
Michael
acceptors
represent
a
class
of
compounds
with
potential
anti-cancer
properties.
They
act
by
binding
to
nucleophilic
sites
in
biological
molecules,
thereby
disrupting
cancer
cell
function
and
inducing
death.
This
mode
action,
as
well
their
ability
be
modified
targeted,
makes
them
promising
avenue
for
advancing
therapy.
We
are
investigating
the
molecular
mechanisms
underlying
interactions
cells,
particular
interfere
cellular
processes
induce
apoptosis.
The
properties
not
accidental
but
due
chemical
structure
reactivity.
electrophilic
nature
these
allows
selectively
target
residues
on
disease-associated
proteins,
resulting
significant
therapeutic
benefits
minimal
toxicity
various
diseases.
opens
up
new
perspectives
development
more
effective
precise
drugs.
Nevertheless,
further
studies
essential
fully
understand
impact
our
discoveries
translate
into
clinical
practice.
Язык: Английский
Unraveling the nexus: Genomic instability and metabolism in cancer
Cell Reports,
Год журнала:
2025,
Номер
44(4), С. 115540 - 115540
Опубликована: Апрель 1, 2025
The
DNA-damage
response
(DDR)
is
a
signaling
network
that
enables
cells
to
detect
and
repair
genomic
damage.
Over
the
past
three
decades,
inhibiting
DDR
has
proven
be
an
effective
cancer
therapeutic
strategy.
Although
drugs
targeting
have
received
approval
for
treating
various
cancers,
tumor
often
develop
resistance
these
therapies,
owing
their
ability
undergo
energetic
metabolic
reprogramming.
Metabolic
intermediates
also
influence
cells'
sense
oxidative
stress,
leading
impaired
redox
metabolism,
thus
creating
vulnerabilities.
In
this
review,
we
summarize
recent
advances
in
understanding
crosstalk
between
metabolism.
We
discuss
combination
therapies
target
DDR,
vulnerabilities
cancer.
outline
potential
obstacles
metabolism
propose
strategies
overcome
challenges.
Язык: Английский
Razing the Scaffolding: The Elimination of Non-Catalytic Functions of Kinases through Targeted Protein Degradation
RSC Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
Overexpression
and
activation
of
kinases
often
results
in
cancer
initiation
progression
through
both
catalytic
non-catalytic
functions
by
promoting
rapid
proliferation,
growth,
survival,
metastasis
cells.
Catalytic
functions...
Язык: Английский
A Medicinal Chemistry Perspective on FDA-Approved Small Molecule Drugs with a Covalent Mechanism of Action
Journal of Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 3, 2025
Covalent
modification
of
disease-driving
proteins
as
a
therapeutic
strategy
has
experienced
well-documented
resurgence
since
2010.
However,
the
earliest
FDA
approval
dates
for
covalent
drugs
are
in
1940s,
although
mechanism
action
may
not
have
been
known
at
time.
This
article
discloses
data
set
all
FDA-approved
small
molecule
acting
via
action,
annotated
by
indication,
biological
target,
reactive
group
on
drug,
partner
(i.e.,
amino
acid
residue,
cofactor,
etc.),
chemical
reaction
mechanism,
bioactivation
requirements,
key
references,
and
reversibility
profile.
We
discuss
these
context
addressing
questions
posed
Merck
Discovery
Chemistry
community
when
considering
series
with
action.
Язык: Английский
Advancements, challenges, and future frontiers in covalent inhibitors and covalent drugs: A review
Muhammad Salman Hameed,
Hongxuan Cao,
Li Guo
и другие.
European Journal of Medicinal Chemistry Reports,
Год журнала:
2024,
Номер
unknown, С. 100217 - 100217
Опубликована: Сен. 1, 2024
Язык: Английский
A photochemical strategy towards Michael addition reactions of cyclopropenes
Опубликована: Авг. 16, 2024
The
development
of
Michael
addition
reactions
to
conjugated
cyclopropenes
is
a
challenge
in
synthesis
due
the
fleeting
and
reactive
nature
such
strained
acceptor
systems.
Herein,
photochemical
approach
towards
reported
that
serves
as
strategic
entry
point
densely
functionalized
cyclopropanes
diastereoselective
fashion.
process
involves
light-mediated
generation
transient
cyclopropenyl
α,β-unsaturated
esters
from
vinyl
diazo
esters,
followed
by
an
organic
base
catalyzed
nucleophilic
N-heterocycles
directly
access
β-N-heterocyclic
cyclopropanoic
esters.
With
this
synergistic
approach,
various
trisubstituted
bearing
N-heteroaryl
N-heterocyclic
rings
indole,
pyrrole,
benzimidazole,
isatin,
pyridinone
quinolinone
were
accessed
efficiently
good
yield
decent
diastereoselectivities.
Further,
β-indolyl
acids
have
been
synthesized
successfully
evaluated
FABP-4
inhibitors.
Theoretical
calculations
performed
elucidate
mechanism
which
was
further
supported
experimental
findings.
Язык: Английский
Mechanism-Based Allylic Carbasugar Chlorides That Form Covalent Intermediates with α- and β-Galactosidases
Molecules,
Год журнала:
2024,
Номер
29(20), С. 4870 - 4870
Опубликована: Окт. 14, 2024
Glycoside
hydrolases
have
been
implicated
in
a
wide
range
of
human
conditions
including
lysosomal
storage
diseases.
Consequently,
many
researchers
directed
their
efforts
towards
identifying
new
classes
glycoside
hydrolase
inhibitors,
both
synthetic
and
from
natural
sources.
A
large
percentage
such
inhibitors
are
reversible
competitive
that
bind
the
active
site
often
due
to
them
possessing
structural
features,
protonatable
basic
nitrogen
atom,
mimic
enzymatic
transition
state.
We
report
mechanism-based
small
molecule
Язык: Английский