Design, synthesis and evaluation of inhibitor of apoptosis protein (IAP) antagonists that are highly selective for the BIR2 domain of XIAP

Bioorg Med Chem Lett. 2013 Jul 15;23(14):4253-7. doi: 10.1016/j.bmcl.2013.04.096. Epub 2013 May 14.

Abstract

We recently reported the systematic ligand-based rational design and synthesis of monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti-apoptotic protein XIAP. Expanded structure-activity relationship (SAR) studies around these peptidomimetics led to compounds with significantly improved selectivity (>60-fold) for the BIR2 domain versus the BIR3 domain of XIAP. The potent and highly selective IAP antagonist 8q (ML183) sensitized TRAIL-resistant prostate cancer cells to apoptotic cell death, highlighting the merit of this probe compound as a valuable tool to investigate the biology of XIAP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Biomimetic Materials / chemical synthesis*
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / toxicity
  • Cell Line, Tumor
  • Cell Survival
  • Drug Design*
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Molecular Docking Simulation
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / toxicity
  • Protein Binding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • ML183 peptide
  • Oligopeptides
  • TNF-Related Apoptosis-Inducing Ligand
  • X-Linked Inhibitor of Apoptosis Protein