Journal of Medicinal Chemistry,
Год журнала:
2022,
Номер
65(11), С. 7415 - 7437
Опубликована: Май 20, 2022
Despite
significant
efficacy,
one
of
the
major
limitations
small-molecule
Bruton's
tyrosine
kinase
(BTK)
agents
is
presence
clinically
acquired
resistance,
which
remains
a
clinical
challenge.
This
Perspective
focuses
on
medicinal
chemistry
strategies
for
development
BTK
inhibitors
against
including
structure-based
design
targeting
point
mutations,
e.g.,
(i)
developing
noncovalent
from
covalent
inhibitors,
(ii)
avoiding
steric
hindrance
mutated
residues,
(iii)
making
interactions
with
residue,
(iv)
modifying
solvent-accessible
region,
and
(v)
new
scaffolds.
Additionally,
comparative
analysis
multi-inhibitions
presented
based
cross-comparisons
between
2916
unique
ligands
283
other
kinases
that
cover
7108
dual/multiple
inhibitions.
Finally,
allosteric
site
uding
proteolysis-targeting
chimera
(PROTAC)
as
two
potential
are
addressed
briefly,
while
also
illustrating
possibilities
challenges
to
find
novel
BTK.
Journal of Medicinal Chemistry,
Год журнала:
2023,
Номер
66(9), С. 6037 - 6046
Опубликована: Апрель 21, 2023
Targeted
protein
degradation
is
a
promising
therapeutic
strategy,
spearheaded
by
the
anti-myeloma
drugs
lenalidomide
and
pomalidomide.
These
stabilize
very
efficiently
complex
between
E3
ligase
Cereblon
(CRBN)
several
non-native
client
proteins
(neo-substrates),
including
transcription
factors
Ikaros
Aiolos
enzyme
Caseine
Kinase
1α
(CK1α,),
resulting
in
their
degradation.
Although
structures
for
these
complexes
have
been
determined,
there
are
no
evident
interactions
that
can
account
high
efficiency
of
formation
ternary
complex.
We
show
lenalidomide's
stabilization
CRBN–CK1α
largely
due
to
hydrophobic
shielding
intermolecular
hydrogen
bonds.
also
find
quantitative
relationship
bond
robustness
binding
affinities
complexes.
results
pave
way
further
understand
cooperativity
effects
drug-induced
protein–protein
could
help
design
improved
molecular
glues
more
efficient
degraders.
Cells,
Год журнала:
2024,
Номер
13(7), С. 578 - 578
Опубликована: Март 26, 2024
Proteolysis-targeting
chimeras
(PROTACs)
describe
compounds
that
bind
to
and
induce
degradation
of
a
target
by
simultaneously
binding
ubiquitin
ligase.
More
generally
referred
as
bifunctional
degraders,
PROTACs
have
led
the
way
in
field
targeted
protein
(TPD),
with
several
currently
undergoing
clinical
testing.
Alongside
single-moiety
compounds,
or
molecular
glue
degraders
(MGDs),
are
increasingly
being
considered
viable
approach
for
development
therapeutics,
driven
advances
rational
discovery
approaches.
This
review
focuses
on
drug
respect
within
proteasome
system,
including
analysis
mechanistic
concepts
approaches,
an
overview
current
pre-clinical
degrader
status
oncology,
neurodegenerative
inflammatory
disease.
Journal of Medicinal Chemistry,
Год журнала:
2022,
Номер
65(11), С. 7415 - 7437
Опубликована: Май 20, 2022
Despite
significant
efficacy,
one
of
the
major
limitations
small-molecule
Bruton's
tyrosine
kinase
(BTK)
agents
is
presence
clinically
acquired
resistance,
which
remains
a
clinical
challenge.
This
Perspective
focuses
on
medicinal
chemistry
strategies
for
development
BTK
inhibitors
against
including
structure-based
design
targeting
point
mutations,
e.g.,
(i)
developing
noncovalent
from
covalent
inhibitors,
(ii)
avoiding
steric
hindrance
mutated
residues,
(iii)
making
interactions
with
residue,
(iv)
modifying
solvent-accessible
region,
and
(v)
new
scaffolds.
Additionally,
comparative
analysis
multi-inhibitions
presented
based
cross-comparisons
between
2916
unique
ligands
283
other
kinases
that
cover
7108
dual/multiple
inhibitions.
Finally,
allosteric
site
uding
proteolysis-targeting
chimera
(PROTAC)
as
two
potential
are
addressed
briefly,
while
also
illustrating
possibilities
challenges
to
find
novel
BTK.
