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Benzazepinones and benzoxazepinones as antagonists of inhibitor of apoptosis proteins (IAPs) selective for the second baculovirus IAP repeat (BIR2) domain.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2013 Oct 24; Vol. 56 (20), pp. 7772-87. Date of Electronic Publication: 2013 Oct 01. - Publication Year :
- 2013
-
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.
- Subjects :
- Alanine analogs & derivatives
Alanine chemical synthesis
Alanine pharmacokinetics
Alanine pharmacology
Animals
Antibodies, Monoclonal pharmacology
Apoptosis drug effects
Blotting, Western
Caspase 3 metabolism
Caspase 7 metabolism
Cell Line, Tumor
Cell Survival drug effects
Crystallography, X-Ray
Female
Heterocyclic Compounds pharmacokinetics
Humans
Inhibitor of Apoptosis Proteins chemistry
Inhibitor of Apoptosis Proteins metabolism
Mice
Mice, Nude
Models, Chemical
Models, Molecular
Molecular Structure
Oxazepines chemical synthesis
Oxazepines pharmacokinetics
Oxazepines pharmacology
Protein Structure, Tertiary
Rats
Ubiquitin-Protein Ligases
X-Linked Inhibitor of Apoptosis Protein chemistry
X-Linked Inhibitor of Apoptosis Protein metabolism
Xenograft Model Antitumor Assays
Heterocyclic Compounds chemical synthesis
Heterocyclic Compounds pharmacology
Inhibitor of Apoptosis Proteins antagonists & inhibitors
X-Linked Inhibitor of Apoptosis Protein antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 56
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24083782
- Full Text :
- https://doi.org/10.1021/jm400731m