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PDBsum entry 5oqw
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PDB id:
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Apoptosis
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Title:
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Xiap in complex with small molecule
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Structure:
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E3 ubiquitin-protein ligase xiap. Chain: a, b. Synonym: baculoviral iap repeat-containing protein 4,iap-like protein,hilp,inhibitor of apoptosis protein 3,hiap3,ring-type e3 ubiquitin transferase xiap,x-linked inhibitor of apoptosis protein,x- linked iap. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: xiap, api3, birc4, iap3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.31Å
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R-factor:
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0.215
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R-free:
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0.246
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Authors:
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P.A.Williams
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Key ref:
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G.A.Ward
et al.
(2018).
ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth.
Mol Cancer Ther,
17,
1381-1391.
PubMed id:
DOI:
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Date:
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14-Aug-17
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Release date:
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27-Jun-18
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PROCHECK
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Headers
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References
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P98170
(XIAP_HUMAN) -
E3 ubiquitin-protein ligase XIAP from Homo sapiens
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Seq:
Struc:
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497 a.a.
106 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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Enzyme class:
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E.C.2.3.2.27
- RING-type E3 ubiquitin transferase.
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Reaction:
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S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6- ubiquitinyl-[acceptor protein]-L-lysine
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DOI no:
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Mol Cancer Ther
17:1381-1391
(2018)
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PubMed id:
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ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth.
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G.A.Ward,
E.J.Lewis,
J.S.Ahn,
C.N.Johnson,
J.F.Lyons,
V.Martins,
J.M.Munck,
S.J.Rich,
T.Smyth,
N.T.Thompson,
P.A.Williams,
N.E.Wilsher,
N.G.Wallis,
G.Chessari.
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ABSTRACT
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Because of their roles in the evasion of apoptosis, inhibitor of apoptosis
proteins (IAP) are considered attractive targets for anticancer therapy.
Antagonists of these proteins have the potential to switch prosurvival signaling
pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with
inherent cIAP selectivity have been tested clinically and demonstrated minimal
single-agent efficacy. ASTX660 is a potent, non-peptidomimetic antagonist of
cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of
XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells, and
in vivo in xenograft models. The compound binds to the isolated BIR3
domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft
tissue, direct antagonism of XIAP was demonstrated by measuring its displacement
from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2,
resulting in downstream effects of NIK stabilization and activation of
noncanonical NF-κB signaling, demonstrated cIAP1/2 antagonism. Treatment with
ASTX660 led to TNFα-dependent induction of apoptosis in various cancer cell
lines in vitro, whereas dosing in mice bearing breast and melanoma tumor
xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase
I-II clinical trial (NCT02503423), and we propose that its antagonism of cIAP1/2
and XIAP may offer improved efficacy over first-generation antagonists that are
more cIAP1/2 selective. Mol Cancer Ther; 17(7); 1381-91. ©2018 AACR.
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