Abstract
Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents.
| Original language | English |
|---|---|
| Pages (from-to) | 6709-6723 |
| Number of pages | 15 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 20 |
| Issue number | 22 |
| DOIs | |
| Publication status | Published - Nov 15 2012 |
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Keywords
- Apoptosis
- IAP inhibitors
- In vitro profiling
- In vivo testing
- Smac mimetics
- Structural studies
ASJC Scopus subject areas
- Pharmaceutical Science
- Drug Discovery
- Organic Chemistry
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry
- Biochemistry
Cite this
Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II : Structural and biological characterization. / Lecis, Daniele; Mastrangelo, Eloise; Belvisi, Laura; Bolognesi, Martino; Civera, Monica; Cossu, Federica; De Cesare, Michelandrea; Delia, Domenico; Drago, Carmelo; Manenti, Giacomo; Manzoni, Leonardo; Milani, Mario; Moroni, Elisabetta; Perego, Paola; Potenza, Donatella; Rizzo, Vincenzo; Scavullo, Cinzia; Scolastico, Carlo; Servida, Federica; Vasile, Francesca; Seneci, Pierfausto.
In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 22, 15.11.2012, p. 6709-6723.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II
T2 - Structural and biological characterization
AU - Lecis, Daniele
AU - Mastrangelo, Eloise
AU - Belvisi, Laura
AU - Bolognesi, Martino
AU - Civera, Monica
AU - Cossu, Federica
AU - De Cesare, Michelandrea
AU - Delia, Domenico
AU - Drago, Carmelo
AU - Manenti, Giacomo
AU - Manzoni, Leonardo
AU - Milani, Mario
AU - Moroni, Elisabetta
AU - Perego, Paola
AU - Potenza, Donatella
AU - Rizzo, Vincenzo
AU - Scavullo, Cinzia
AU - Scolastico, Carlo
AU - Servida, Federica
AU - Vasile, Francesca
AU - Seneci, Pierfausto
PY - 2012/11/15
Y1 - 2012/11/15
N2 - Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents.
AB - Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents.
KW - Apoptosis
KW - IAP inhibitors
KW - In vitro profiling
KW - In vivo testing
KW - Smac mimetics
KW - Structural studies
UR - http://www.scopus.com/inward/record.url?scp=84867863403&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867863403&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2012.09.041
DO - 10.1016/j.bmc.2012.09.041
M3 - Article
C2 - 23062821
AN - SCOPUS:84867863403
VL - 20
SP - 6709
EP - 6723
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 22
ER -