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

Access to Document

10.1016/j.bmc.2012.09.041

Fingerprint Dive into the research topics of 'Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization'. Together they form a unique fingerprint.

Cite this

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.

@article{58e44bfd631e41df9ffbf0cdd274d27e,

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

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.",

keywords = "Apoptosis, IAP inhibitors, In vitro profiling, In vivo testing, Smac mimetics, Structural studies",

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

year = "2012",

month = nov,

day = "15",

doi = "10.1016/j.bmc.2012.09.041",

language = "English",

volume = "20",

pages = "6709--6723",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Limited",

number = "22",

}

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 -