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

Research output: Contribution to journalArticlepeer-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 languageEnglish
Pages (from-to)6709-6723
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number22
DOIs
Publication statusPublished - 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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