Abstract
Nonpeptidic, bivalent Smac mimetics designed based upon monovalent Smac mimetics with a diazabicyclic core structure bind to XIAP, cIAP1, and cIAP2 with low to subnanomolar affinities and are highly effective in antagonizing XIAP in cell-free functional assays. They efficiently induce the degradation of cIAP1 and cIAP2 in cancer cells at concentrations as low as 1 nM, activate caspase-3 and -8, and cleave PARP at 3-10 nM. The most potent compounds in the series have IC(50) of 3-5 nM in inhibition of cell growth in both MDA-MB-231 and SK-OV-3 cell lines and are promising lead compounds for the development of a new class of cancer therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Aza Compounds / chemical synthesis*
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Aza Compounds / chemistry
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Aza Compounds / pharmacology
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Caspase 3 / metabolism
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Caspase 9 / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Screening Assays, Antitumor
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Enzyme Activation / drug effects
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Humans
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
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Models, Molecular
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Oligopeptides / chemistry*
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Peptidomimetics / chemical synthesis*
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Peptidomimetics / chemistry
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Peptidomimetics / pharmacology
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Poly(ADP-ribose) Polymerases / metabolism
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Protein Binding
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Structure-Activity Relationship
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X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors
Substances
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Antineoplastic Agents
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Aza Compounds
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Inhibitor of Apoptosis Proteins
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Oligopeptides
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Peptidomimetics
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SMAC peptide
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X-Linked Inhibitor of Apoptosis Protein
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Poly(ADP-ribose) Polymerases
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Caspase 3
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Caspase 9