Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization

Daniele Lecis; Eloise Mastrangelo; Laura Belvisi; Martino Bolognesi; Monica Civera; Federica Cossu; Michelandrea De Cesare; Domenico Delia; Carmelo Drago; Giacomo Manenti; Leonardo Manzoni; Mario Milani; Elisabetta Moroni; Paola Perego; Donatella Potenza; Vincenzo Rizzo; Cinzia Scavullo; Carlo Scolastico; Federica Servida; Francesca Vasile; Pierfausto Seneci

doi:10.1016/j.bmc.2012.09.041

Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization

Daniele Lecis, Eloise Mastrangelo, Laura Belvisi, Martino Bolognesi, Monica Civera, Federica Cossu, Michelandrea De Cesare, Domenico Delia, Carmelo Drago, Giacomo Manenti, Leonardo Manzoni, Mario Milani, Elisabetta Moroni, Paola Perego, Donatella Potenza, Vincenzo Rizzo, Cinzia Scavullo, Carlo Scolastico, Federica Servida, Francesca VasilePierfausto Seneci

Fondazione IRCCS Istituto Nazionale dei Tumori

Research output: Contribution to journal › Article › peer-review

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	https://doi.org/10.1016/j.bmc.2012.09.041
Publication status	Published - Nov 15 2012

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

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10.1016/j.bmc.2012.09.041

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Lecis, D., Mastrangelo, E., Belvisi, L., Bolognesi, M., Civera, M., Cossu, F., De Cesare, M., Delia, D., Drago, C., Manenti, G., Manzoni, L., Milani, M., Moroni, E., Perego, P., Potenza, D., Rizzo, V., Scavullo, C., Scolastico, C., Servida, F., ... Seneci, P. (2012). Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization. Bioorganic and Medicinal Chemistry, 20(22), 6709-6723. https://doi.org/10.1016/j.bmc.2012.09.041

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 › peer-review

Lecis, D, Mastrangelo, E, Belvisi, L, Bolognesi, M, Civera, M, Cossu, F, De Cesare, M, Delia, D, Drago, C, Manenti, G, Manzoni, L, Milani, M, Moroni, E, Perego, P, Potenza, D, Rizzo, V, Scavullo, C, Scolastico, C, Servida, F, Vasile, F & Seneci, P 2012, 'Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization', Bioorganic and Medicinal Chemistry, vol. 20, no. 22, pp. 6709-6723. https://doi.org/10.1016/j.bmc.2012.09.041

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. / Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II : Structural and biological characterization. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 22. pp. 6709-6723.

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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.",

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AU - Scavullo, Cinzia

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Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization

Abstract

Keywords

ASJC Scopus subject areas

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