Abstract
XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain and bind to cIAP1 and cIAP2 as well as XIAP. Pathways activated upon cIAP binding contribute to the function of these compounds. Inhibitors selective for XIAP should exert pro-apoptotic effects through competition with the terminal caspases. This paper details our synthetic explorations of a novel XIAP BIR2-selective benzazepinone screening hit with a focus on increasing BIR2 potency and overcoming high in vivo clearance. These efforts led to the discovery of benzoxazepinone 40, a potent BIR2-selective inhibitor with good in vivo pharmacokinetic properties which potentiates apoptotic signaling in a manner mechanistically distinct from that of known pan-IAP inhibitors.
MeSH terms
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Alanine / analogs & derivatives
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Alanine / chemical synthesis
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Alanine / pharmacokinetics
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Alanine / pharmacology
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Animals
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Antibodies, Monoclonal / pharmacology
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Apoptosis / drug effects
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Blotting, Western
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Caspase 3 / metabolism
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Caspase 7 / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Crystallography, X-Ray
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Female
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Heterocyclic Compounds / chemical synthesis*
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Heterocyclic Compounds / pharmacokinetics
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Heterocyclic Compounds / pharmacology*
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Humans
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
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Inhibitor of Apoptosis Proteins / chemistry
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Inhibitor of Apoptosis Proteins / metabolism
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Mice
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Mice, Nude
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Models, Chemical
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Models, Molecular
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Molecular Structure
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Oxazepines / chemical synthesis
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Oxazepines / pharmacokinetics
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Oxazepines / pharmacology
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Protein Structure, Tertiary
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Rats
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Ubiquitin-Protein Ligases
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X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
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X-Linked Inhibitor of Apoptosis Protein / chemistry
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X-Linked Inhibitor of Apoptosis Protein / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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Heterocyclic Compounds
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Inhibitor of Apoptosis Proteins
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N-(5-((2-cyano-1-(2-cyanophenyl)-1H-indol-3-yl)methyl)-4-oxo-2',3',4,5,5',6'-hexahydro-3H-spiro(benzo(b)(1,4)oxazepine-2,4'-pyran)-3-yl)-2-(methylamino)propanamide
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Oxazepines
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X-Linked Inhibitor of Apoptosis Protein
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conatumumab
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BIRC2 protein, human
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Ubiquitin-Protein Ligases
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Caspase 3
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Caspase 7
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Alanine