 |
PDBsum entry 4r02
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
4r02
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
250 a.a.
|
|
|
|
|
|
|
|
|
|
|
244 a.a.
|
|
|
|
|
|
|
|
|
|
|
240 a.a.
|
|
|
|
|
|
|
|
|
|
|
235 a.a.
|
|
|
|
|
|
|
|
|
|
|
231 a.a.
|
|
|
|
|
|
|
|
|
|
|
243 a.a.
|
|
|
|
|
|
|
|
|
|
|
241 a.a.
|
|
|
|
|
|
|
|
|
|
|
226 a.a.
|
|
|
|
|
|
|
|
|
|
|
204 a.a.
|
|
|
|
|
|
|
|
|
|
|
195 a.a.
|
|
|
|
|
|
|
|
|
|
|
212 a.a.
|
|
|
|
|
|
|
|
|
|
|
222 a.a.
|
|
|
|
|
|
|
|
|
|
|
233 a.a.
|
|
|
|
|
|
|
|
|
|
|
196 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
α-Keto phenylamides as p1'-Extended proteasome inhibitors.
|
|
|
Authors
|
|
C.Voss,
C.Scholz,
S.Knorr,
P.Beck,
M.L.Stein,
A.Zall,
U.Kuckelkorn,
P.M.Kloetzel,
M.Groll,
K.Hamacher,
B.Schmidt.
|
|
|
Ref.
|
|
Chemmedchem, 2014,
9,
2557-2564.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The major challenge for proteasome inhibitor design lies in achieving high
selectivity for, and activity against, the target, which requires specific
interactions with the active site. Novel ligands aim to overcome
off-target-related side effects such as peripheral neuropathy, which is
frequently observed in cancer patients treated with the FDA-approved proteasome
inhibitors bortezomib (1) or carfilzomib (2). A systematic comparison of
electrophilic headgroups recently identified the class of α-keto amides as
promising for next generation drug development. On the basis of crystallographic
knowledge, we were able to develop a structure-activity relationship (SAR)-based
approach for rational ligand design using an electronic parameter (Hammett's σ)
and in silico molecular modeling. This resulted in the tripeptidic α-keto
phenylamide BSc4999
[(S)-3-(benzyloxycarbonyl-(S)-leucyl-(S)-leucylamino)-5-methyl-2-oxo-N-(2,4-dimethylphenyl)hexanamide,
6 a], a highly potent (IC50 =38 nM), cell-permeable, and slowly reversible
covalent inhibitor which targets both the primed and non-primed sites of the
proteasome's substrate binding channel as a special criterion for selectivity.
The improved inhibition potency and selectivity of this new α-keto phenylamide
makes it a promising candidate for targeting a wider range of tumor subtypes
than commercially available proteasome inhibitors and presents a new candidate
for future studies.
|
|
|
|
|
|
|
