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Drug-Target Interaction

Drug

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PubChem ID:70726
Structure:
Synonyms:
1121-89-7
178098_ALDRICH
2,6-Diketopiperidine
2,6-Piperidinedione
2,6-Piperidinedione (9CI)
2,6-Piperidinedione, 4-(2-(3,5-dimethyl-2-oxocyclohexyl)-2-hydroxyethyl)-, (1S-(1alpha(S*),3alpha,5beta))-
5-21-09-00557 (Beilstein Handbook Reference)
66-81-9
AB1002174
AC1L2EPY
AC1Q6G7X
Actidione
AIDS-081864
AIDS081864
AR-1D5144
BRN 0110052
C07275
CHEBI:5435
Cicloheximide
Cycloheximide
D003513
EINECS 214-340-4
G0269
Glutarimide
LS-72007
NSC 58190
NSC58190
Piperidine-2,6-dione
S14-1464
ST51056669
ZINC01530742

Target

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Uniprot ID:ICE_DROME
Synonyms:
Caspase
drICE
EC-Numbers:3.4.22.-
Organism:Drosophila melanogaster
Fruit fly
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----

References:

16357160
Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells.. Steffan T Nawrocki; Jennifer S Carew; Kenneth DunnerJr; Lawrence H Boise; Paul J Chiao; Peng Huang; James L Abbruzzese; David J McConkey (2005) Cancer research display abstract
Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative that is a selective and potent inhibitor of the proteasome. We hypothesized that proteasome inhibition would lead to an accumulation of misfolded proteins in the cell resulting in endoplasmic reticulum (ER) stress. The ability of bortezomib to induce ER stress and the unfolded protein response was investigated in a human pancreatic cancer cell line, L3.6pl. Bortezomib increased expression of ER stress markers, CHOP and BiP, but inhibited PKR-like ER kinase and subsequent phosphorylation of eukaryotic initiation factor 2alpha (eif2alpha), both of which are key events in translational suppression. These effects resulted in an accumulation of ubiquitylated proteins leading to protein aggregation and proteotoxicity. Peptide inhibitor or small interfering RNA targeting ER-resident caspase-4 blocked DNA fragmentation, establishing a central role for caspase-4 in bortezomib-induced cell death. The translation inhibitor cycloheximide abrogated bortezomib-induced protein aggregation, caspase-4 processing, and all other characteristics of apoptosis. Because malignant cells have higher protein synthesis rates than normal cells, they may be more prone to protein aggregation and proteotoxicity and possess increased sensitivity to bortezomib-induced apoptosis. Taken together, the results show that bortezomib induces a unique type of ER stress compared with other ER stress agents characterized by an absence of eif2alpha phosphorylation, ubiquitylated protein accumulation, and proteotoxicity.