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

  • Bioorg Med Chem. 2012 Nov 15;20(22):6709-23. doi: 10.1016/j.bmc.2012.09.041.
Daniele Lecis  1 ,  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
Affiliations
  • 1. Dipartimento di Oncologia Sperimentale e Medicina Molecolare, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milan, Italy.
PMID: 23062821 DOI: 10.1016/j.bmc.2012.09.041
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.