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.
Copyright © 2012 Elsevier Ltd. All rights reserved.