Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2

Federica Cossu, Eloise Mastrangelo, Mario Milani, Graziella Sorrentino, Daniele Lecis, Domenico Delia, Leonardo Manzoni, Pierfausto Seneci, Carlo Scolastico, Martino Bolognesi

Research output: Contribution to journalArticle

Abstract

Inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2 are upregulated in many cancer cells. Several compounds targeting IAPs and inducing cell death in cancer cells have been developed. Some of these are synthesized mimicking the N-terminal tetrapeptide sequence of Smac/DIABLO, the natural endogenous IAPs inhibitor. Starting from such conceptual design, we generated a library of 4-substituted azabicyclo[5.3.0]alkane Smac-mimetics. Here we report the crystal structure of the BIR3 domain from XIAP in complex with Smac037, a compound designed according to structural principles emerging from our previously analyzed XIAP BIR3/Smac-mimetic complexes. In parallel, we present an in silico docking analysis of three Smac-mimetics to the BIR3 domain of cIAP1, providing general considerations for the development of high affinity lead compounds targeting three members of the IAP family.

Original languageEnglish
Pages (from-to)162-167
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume378
Issue number2
DOIs
Publication statusPublished - Jan 9 2009

Keywords

  • cIAP
  • Inhibition of apoptosis
  • Oncology
  • Peptidomimetics
  • SMAC/DIABLO
  • XIAP

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

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  • Cite this

    Cossu, F., Mastrangelo, E., Milani, M., Sorrentino, G., Lecis, D., Delia, D., Manzoni, L., Seneci, P., Scolastico, C., & Bolognesi, M. (2009). Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2. Biochemical and Biophysical Research Communications, 378(2), 162-167. https://doi.org/10.1016/j.bbrc.2008.10.139