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PDBsum entry 4inu
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Hydrolase/hydrolase inhibitor
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PDB id
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4inu
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Contents |
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250 a.a.
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244 a.a.
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241 a.a.
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242 a.a.
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233 a.a.
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244 a.a.
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243 a.a.
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222 a.a.
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204 a.a.
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198 a.a.
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212 a.a.
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222 a.a.
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233 a.a.
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196 a.a.
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References listed in PDB file
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Key reference
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Title
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Incorporation of non-Natural amino acids improves cell permeability and potency of specific inhibitors of proteasome trypsin-Like sites.
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Authors
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P.P.Geurink,
W.A.Van der linden,
A.C.Mirabella,
N.Gallastegui,
G.De bruin,
A.E.Blom,
M.J.Voges,
E.D.Mock,
B.I.Florea,
G.A.Van der marel,
C.Driessen,
M.Van der stelt,
M.Groll,
H.S.Overkleeft,
A.F.Kisselev.
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Ref.
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J Med Chem, 2013,
56,
1262-1275.
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PubMed id
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Abstract
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Proteasomes degrade the majority of proteins in mammalian cells by a concerted
action of three distinct pairs of active sites. The chymotrypsin-like sites are
targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the
trypsin-like site sensitize multiple myeloma cells to these agents. Here we
describe systematic effort to develop inhibitors with improved potency and cell
permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone
(4a, LU-102), and a fluorescent activity-based probe for this site. X-ray
structures of 4a and related inhibitors complexed with yeast proteasomes
revealed the structural basis for specificity. Nontoxic to myeloma cells when
used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This
sensitizing effect was much stronger than the synergistic effects of histone
acetylase inhibitors or additive effects of doxorubicin and dexamethasone,
raising the possibility that combinations of inhibitors of the trypsin-like site
with bortezomib or carfilzomib would have stronger antineoplastic activity than
combinations currently used clinically.
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