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PDBsum entry 4eu2
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Hydrolase/hydrolase inhibitor
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PDB id
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4eu2
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Contents |
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241 a.a.
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249 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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232 a.a.
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244 a.a.
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196 a.a.
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222 a.a.
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204 a.a.
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196 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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References listed in PDB file
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Key reference
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Title
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Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding.
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Authors
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J.Kikuchi,
N.Shibayama,
S.Yamada,
T.Wada,
M.Nobuyoshi,
T.Izumi,
M.Akutsu,
Y.Kano,
K.Sugiyama,
M.Ohki,
S.Y.Park,
Y.Furukawa.
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Ref.
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Plos One, 2013,
8,
e60649.
[DOI no: ]
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PubMed id
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Abstract
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The proteasome is a proteolytic machinery that executes the degradation of
polyubiquitinated proteins to maintain cellular homeostasis. Proteasome
inhibition is a unique and effective way to kill cancer cells because they are
sensitive to proteotoxic stress. Indeed, the proteasome inhibitor bortezomib is
now indispensable for the treatment of multiple myeloma and other intractable
malignancies, but is associated with patient inconvenience due to intravenous
injection and emerging drug resistance. To resolve these problems, we attempted
to develop orally bioavailable proteasome inhibitors with distinct mechanisms of
action and identified homopiperazine derivatives (HPDs) as promising candidates.
Biochemical and crystallographic studies revealed that some HPDs inhibit all
three catalytic subunits (ß 1, ß 2 and ß 5) of the proteasome by direct
binding, whereas bortezomib and other proteasome inhibitors mainly act on the
ß5 subunit. Proteasome-inhibitory HPDs exhibited cytotoxic effects on cell
lines from various hematological malignancies including myeloma. Furthermore,
K-7174, one of the HPDs, was able to inhibit the growth of bortezomib-resistant
myeloma cells carrying a ß5-subunit mutation. Finally, K-7174 had additive
effects with bortezomib on proteasome inhibition and apoptosis induction in
myeloma cells. Taken together, HPDs could be a new class of proteasome
inhibitors, which compensate for the weak points of conventional ones and
overcome the resistance to bortezomib.
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