Abstract
A potent, cell-permeable, conformationally constrained second mitochondria derived activator of caspase mimetic (SM-131, 2) has been designed, synthesized, and evaluated. Compound 2 binds to X-linked inhibitors of apoptosis proteins (XIAP) with a Ki of 61 nM in a competitive binding assay and directly antagonizes the XIAP inhibition of caspase-9 activity in a cell-free functional assay. Compound 2 achieves an IC50 of 100 nM in inhibition of cell growth and effectively induces cell death in the MDA-MB-231 human breast cancer cell line.
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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Azepines / chemical synthesis*
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Azepines / chemistry
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Azepines / pharmacology*
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Baculoviral IAP Repeat-Containing 3 Protein
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Binding, Competitive
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Caspase 3 / metabolism*
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Caspase 9 / metabolism*
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Caspase Inhibitors
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Cell Death / drug effects
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Cell Membrane Permeability
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Cell Proliferation / drug effects
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Enzyme Activation / drug effects*
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Heterocyclic Compounds / chemical synthesis*
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacology*
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Humans
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Inhibitor of Apoptosis Proteins / metabolism
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Models, Molecular
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Molecular Conformation
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Molecular Mimicry*
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Protein Binding
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology*
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Structure-Activity Relationship
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Tumor Cells, Cultured
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Ubiquitin-Protein Ligases
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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6-(2-methylaminobutyrylamino)-5-oxooctahydropyrrolo(1,2-a)azepine-3-carboxylic acid
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Azepines
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Caspase Inhibitors
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Heterocyclic Compounds
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Inhibitor of Apoptosis Proteins
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Pyrrolidines
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X-Linked Inhibitor of Apoptosis Protein
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BIRC3 protein, human
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Baculoviral IAP Repeat-Containing 3 Protein
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Ubiquitin-Protein Ligases
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Caspase 3
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Caspase 9