Abstract
We describe the synthesis and properties of a small molecule mimic of Smac, a pro-apoptotic protein that functions by relieving inhibitor-of-apoptosis protein (IAP)-mediated suppression of caspase activity. The compound binds to X chromosome- encoded IAP (XIAP), cellular IAP 1 (cIAP-1), and cellular IAP 2 (cIAP-2) and synergizes with both tumor necrosis factor alpha (TNFalpha) and TNF-related apoptosis-inducing ligand (TRAIL) to potently induce caspase activation and apoptosis in human cancer cells. The molecule has allowed a temporal, unbiased evaluation of the roles that IAP proteins play during signaling from TRAIL and TNF receptors. The compound is also a lead structure for the development of IAP antagonists potentially useful as therapy for cancer and inflammatory diseases.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkynes / chemical synthesis
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Alkynes / chemistry
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Alkynes / metabolism
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Alkynes / pharmacology*
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Apoptosis Regulatory Proteins
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Apoptosis*
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Biotinylation
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Carrier Proteins* / chemistry
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Carrier Proteins* / metabolism
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Caspase Inhibitors
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Caspases / metabolism
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Cell Line, Tumor
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Computer Simulation
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Dimerization
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Dipeptides / chemical synthesis
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Dipeptides / chemistry
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Dipeptides / metabolism
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Dipeptides / pharmacology*
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Diynes
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Glioblastoma
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Humans
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / pharmacology*
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Mitochondrial Proteins* / chemistry
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Mitochondrial Proteins* / metabolism
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Molecular Mimicry*
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NF-kappa B / metabolism
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Poly(ADP-ribose) Polymerases / metabolism
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Protein Binding
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Protein Conformation
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Protein Engineering
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Proteins / metabolism
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Signal Transduction
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TNF-Related Apoptosis-Inducing Ligand
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Tetrazoles / chemical synthesis
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Tetrazoles / chemistry
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Tetrazoles / metabolism
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Tetrazoles / pharmacology*
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology*
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X-Linked Inhibitor of Apoptosis Protein
Substances
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1,6-bis(4,7-diaza-6-methyl-5-oxo-3-((2-((5-(phenylthio)tetrazol-1-yl)methyl)pyrrolidin-1-yl)carbonyl)octyloxy)-2,4-hexadiyne
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Alkynes
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Apoptosis Regulatory Proteins
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Carrier Proteins
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Caspase Inhibitors
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DIABLO protein, human
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Dipeptides
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Diynes
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Mitochondrial Proteins
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NF-kappa B
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Proteins
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RMT5265
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tetrazoles
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Tumor Necrosis Factor-alpha
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Poly(ADP-ribose) Polymerases
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Caspases