Abstract
A successful structure-based design of conformationally constrained second mitochondria-derived activator of caspase (Smac) mimetics that target the XIAP/caspase-9 interaction site is described. The most potent Smac mimetic 12d has a Ki of 350 nM for binding to the XIAP BIR3 domain protein. 12d is found to be effective in enhancing apoptosis induced by cisplatin in PC-3 human prostate cancer cells.
Copyright 2004 American Chemical Society
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins
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Carrier Proteins / chemistry*
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Caspase 9
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Caspases / metabolism*
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Cell Line, Tumor
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Cyclization
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Heterocyclic Compounds, 2-Ring / chemical synthesis*
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Heterocyclic Compounds, 2-Ring / chemistry
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Heterocyclic Compounds, 2-Ring / pharmacology
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Humans
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins / chemistry*
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Models, Molecular
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Molecular Conformation
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Molecular Mimicry
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Oligopeptides / chemistry*
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Protein Binding
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Protein Structure, Tertiary
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Proteins / metabolism*
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Structure-Activity Relationship
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X-Linked Inhibitor of Apoptosis Protein
Substances
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Apoptosis Regulatory Proteins
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Carrier Proteins
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DIABLO protein, human
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Heterocyclic Compounds, 2-Ring
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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Oligopeptides
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Proteins
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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CASP9 protein, human
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Caspase 9
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Caspases