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Title
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Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs.
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Authors
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K.Zobel,
L.Wang,
E.Varfolomeev,
M.C.Franklin,
L.O.Elliott,
H.J.Wallweber,
D.C.Okawa,
J.A.Flygare,
D.Vucic,
W.J.Fairbrother,
K.Deshayes.
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Ref.
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Acs Chem Biol, 2006,
1,
525-533.
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PubMed id
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Abstract
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Designed second mitochondrial activator of caspases (Smac) mimetics based on an
accessible [7,5]-bicyclic scaffold bind to and antagonize protein interactions
involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP
(XIAP), melanoma IAP (ML-IAP), and c-IAPs 1 and 2 (cIAP1 and cIAP2). The design
rationale is based on a combination of phage-panning data, peptide binding
studies, and a survey of potential isosteres. The synthesis of two scaffolds is
described. These compounds bind the XIAP-baculoviral IAP repeat 3 (BIR3),
cIAP1-BIR3, cIAP2-BIR3, and ML-IAP-BIR domains with submicromolar affinities.
The most potent Smac mimetic binds the cIAP1-BIR3 and ML-IAP-BIR domains with a
K i of 50 nM. The X-ray crystal structure of this compound bound to an
ML-IAP/XIAP chimeric BIR domain protein is compared with that of a complex with
a phage-derived tetrapeptide, AVPW. The structures show that these compounds
bind to the Smac-binding site on ML-IAP with identical hydrogen-bonding patterns
and similar hydrophobic interactions. Consistent with the structural data,
coimmunoprecipitation experiments demonstrate that the compounds can effectively
block Smac interactions with ML-IAP. The compounds are further demonstrated to
activate caspase-3 and -7, to reduce cell viability in assays using MDA-MB-231
breast cancer cells and A2058 melanoma cells, and to enhance doxorubicin-induced
apoptosis in MDA-MB-231 cells.
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